110 / Advanced Therapy in Thoracic Surgery term survivor is more likely to have a second primary malignancy than a relapse of the small cell lung cancer, and many of these new tumors arise in the lung In the University of Toronto series, eight patients underwent surgical resection at the time of “relapse” following a long disease-free interval after initial treatment for small cell lung cancer Two were found to have nonsmall cell tumors, and both achieved long-term survival after surgery It is recommended, therefore, that a biopsy should be undertaken for long-term survivors of small cell lung cancer who develop a new lung lesion If nonsmall cell pathology is documented, the patient should be staged completely, and surgery should be considered if the standard medical and surgical criteria for resection that would be applied to all patients with nonsmall cell tumors are met tified at diagnosis, the initial treatment should be chemotherapy to control the small cell component of the disease, and surgery should be considered for the nonsmall cell component For patients who demonstrate an unexpectedly poor response to chemotherapy, and for those who experience localized late relapse after treatment for pure small cell tumors, a repeat biopsy should be performed Surgery may be considered if nonsmall cell pathology is confirmed Summary Mountain C Clinical biology of small cell carcinoma: relationship to surgical therapy Semin Oncol 1978;5:272–9 Combined modality therapy with surger y and chemotherapy is feasible; the toxicity is manageable and postoperative morbidity and mortality rates acceptable Patient selection is important, and the results of the LCSG trial indicate that surgical resection does not benefit the majority of patients with limited small cell lung cancer The chances of long-term survival and cure are strongly correlated with pathologic TNM subgroups, and consideration of surgery for patients with small cell lung cancer should be limited to those with stage I and perhaps stage II cancer Therefore, before surgery is undertaken, patients should undergo full staging of the mediastinum, including mediastinoscopy Surgery may be considered for patients with T1–2N0 small cell tumors, and whether it is offered as the initial treatment or after induction chemotherapy does not seem to be important, as has been shown by Wada and colleagues and the University of Toronto Group.28,34 If a small cell tumor is identified unexpectedly at the time of thoracotomy, complete resection and mediastinal lymph node resection should be undertaken if possible Chemotherapy is recommended postoperatively for all patients, even those with pathologic stage I tumors Surgery likely has very little role to play for most patients with stage II tumors and virtually no role for those with stage III tumors Even though chemotherapy can result in dramatic shrinkage of bulky mediastinal tumors, the addition of surgical resection does not contribute significantly to long-term survival for the majority of patients, as has been shown conclusively by the LCSG trial The final group of patients who may benefit from surgical resection are those with combined small cell and nonsmall cell tumors If a mixed histology cancer is iden- References Hansen HH, Dombernowsky P, Hirsch FR Staging procedures and prognostic features in small cell anaplastic bronchogenic carcinoma Semin Oncol 1978;5:280–7 Martini N, Wittes RE, Hilaris BS, et al Oat cell carcinoma of the lung Clin Bull 1975;5:144–8 Working Party on the Evaluation of Different Methods of Therapy in Carcinoma of the Bronchus Comparative trial of surgery and radiotherapy for the primary treatment of small celled, or oat-celled carcinoma of the bronchus Lancet 1966;2:979–86 Fox W, Scadding JG Medical research council comparative trial of surgery and radiotherapy for primary treatment of small celled or oat-celled carcinoma of the bronchus Tenyear follow-up Lancet 1973;2:63–5 Bates M, Levison V, Hurt R, Sutton M Treatment of oat-cell carcinoma of bronchus by pre-operative radiotherapy and surgery Lancet 1975;1:1134–5 Levison V Pre-operative radiotherapy and surgery in the treatment of oat-cell carcinoma of the bronchus Clin Radiol 1980;31:345–8 Sherman DM, Neptune W, Weichselbaum R, et al An aggressive approach to marginally resectable lung cancer Cancer 1978;41:2040–5 Bergsagel DE, Jenkin RDT, Pringle JF Lung cancer: clinical trial of radiotherapy alone versus radiotherapy plus cyclophosphamide Cancer 1972;30:321 10 Medical Research Council Lung Cancer Working Party Radiotherapy alone or with chemotherapy in the treatment of small cell carcinoma of the lung Br J Cancer 1979;40:1–10 11 Shields TW, Humphrey EW, Eastridge CE, Keehn RJ Adjuvant cancer chemotherapy after resection of carcinoma of the lung Cancer 1977;40:2057–62 12 Shields TW, Higgins GA, Matthews MG, Keehn RJ Surgical resection in the management of small cell carcinoma of the lung J Thorac Cardiovasc Surg 1982;84:481–8 13 Shore DF, Paneth M Survival after resection of small cell carcinoma of the bronchus Thorax 1987;35:819–22 Surgical Management of Small Cell Lung Cancer / 111 14 Lennox SC, Flavell G, Pollock DJ, et al Results of resection for oat-cell carcinoma of the lung Lancet 1968;2:925–7 15 Higgins GS, Shields TW, Keehn RJ The solidary pulmonary nodule Ten-year follow-up of Veterans Administration–Armed Forces Co-operative study Arch Surg 1975;110:570–5 16 Shepherd FA The role of chemotherapy in the treatment of small cell lung cancer Chest Surg Clin N Am 1997;7:113–33 17 Elliott JA, Osterlind K, Hirsch FR, Hansen HH Metastatic patterns in small cell lung cancer: correlation of autopsy findings with clinical parameters in 537 patients J Clin Oncol 1987;5:246–54 18 Warde P, Payne D Does thoracic irradiation improve survival and local control in limited-stage small cell carcinoma of the lung? A meta-analysis J Clin Oncol 1992;10:890–5 19 Pingnon J-P, Arriagada R, Ihde D, et al A meta-analysis of thoracic radiotherapy for small cell lung cancer N Engl J Med 1992;327:1618–24 20 Murray N, Coy P, Pater J, et al Importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small cell lung cancer J Clin Oncol 1993;11:336–44 21 Shepherd FA, Ginsberg RJ, Evans WK, et al Reduction in local recurrence and improved survival in surgically treated patients with small cell lung cancer J Thorac Cardiovasc Surg 1983;86:498–504 30 Osterlind K, Hansen HH, Hansen M, et al Mortality and morbidity in long-term surviving patients treated with chemotherapy with or without irradiation for small cell lung cancer J Clin Oncol 1986;4:1044–52 31 Hayata Y, Funatsu H, Suemasu K, et al Surgical indications for small cell carcinoma of the lung Jpn J Clin Oncol 1978;8:93–100 32 Meyer J, Comis RL, Ginsberg SJ, et al The prospect of disease control by surgery combined with chemotherapy in stage I and stage II small cell carcinoma of the lung Ann Thorac Surg 1983;36:37–43 33 Meyer JA, Gullo JJ, Ikins PM, et al Adverse prognostic effect of N2 disease in treated small cell carcinoma of the lung J Thorac Cardiovasc Surg 1984;88:495–501 34 Wada H, Yokomise H, Tanaka F, et al Surgical treatment of small cell carcinoma of the lung: advantage of preoperative chemotherapy Lung Cancer 1995;13:45–56 35 Osterlind K, Hansen M, Hansen HH, Dombernowsky P Influence of surgical resection prior to chemotherapy on the long-term results in small cell lung cancer A study of 150 operable patients Eur J Cancer Clin Oncol 1986;22:589–93 36 Maassen W, Greschuchna D Small cell carcinoma of the lung—to operate or not? Surgical experience and results Thorac Cardiovasc Surg 1986;34:71–6 37 Shepherd FA, Evans WK, Feld R, et al Adjuvant chemotherapy following surgical resection for small cell carcinoma of the lung J Clin Oncol 1988;6:832–8 22 Comis R, Meyer J, Ginsberg S, et al The impact of TNM stage on results with chemotherapy and adjuvant surgery in small cell lung cancer [abstract C-844] Proc Am Soc Clin Oncol 1984;3:226 38 Karrer K, Denck H, Karnicka-Mlodkowska H, et al The importance of surgery as the first step in multi-modality treatment of small cell bronchial carcinoma Int J Clin Pharmacol Res 1990;10:257–63 23 Hirsch FR, Osterlind K, Hansen H The prognostic significance of histopathologic subtyping of small cell carcinoma of the lung according to the classification of the World Health Organization Cancer 1983;52:2144–50 39 Ulsperger E, Karrer K, Denck H ISC-lung cancer study group Multi-modality treatment for small cell bronchial carcinoma Eur J Cardiothorac Surg 1991;5:306–10 24 Magnum MD, Greco FA, Hainsworth JD, et al Combined small cell and non-small cell lung cancer J Clin Oncol 1989;7:607–12 25 Shepherd FA, Ginsberg RJ, Feld R, et al Surgical treatment for limited small cell lung cancer J Thorac Cardiovasc Surg 1991;101:385–93 26 Heyne KH, Lippman SM, Lee JJ, et al The incidence of second primary tumors in long-term survivors of small cell lung cancer J Clin Oncol 1992;10:1519–24 40 Macchiarini P, Hardin M, Basolo F, et al Surgery plus adjuvant chemotherapy for T1–3N0M0 small cell lung cancer Am J Clin Oncol 1991;14:218–24 41 Hara N, Ichinose Y, Kuda T, et al Long-term survivors in resected and non-resected small cell lung cancer Oncology 1991;48:441–7 42 Davis S, Crino L, Tonato M, et al A prospective analysis of chemotherapy following surgical resection of clinical stage I–II small cell lung cancer Am J Clin Oncol 1993;16:93–5 27 Tucker MA, Murray N, Shaw EG, et al Second cancers related to smoking and treatment for small cell lung cancer J Natl Cancer Inst 1997;89:1782–8 43 Friess GG, McCracken JD, Troxell ML, et al Effects of initial resection of small cell carcinoma of the lung: a review of Southwest Oncology Group study 7628 J Clin Oncol 1985;3:964–8 28 Sagman U, Lishner M, Maki E, et al Second primary malignancies following diagnosis of small cell lung cancer J Clin Oncol 1992;10:1525–33 44 Littlewood TH, Smith AP, Bentley DP Treatment of small cell lung cancer by pneumonectomy and single course high dose chemotherapy Thorax 1987;42:315–6 29 Ihde DC, Tucker MA Second primary malignancies in small cell lung cancer: a major consequence of modest success J Clin Oncol 1992;10:1511–3 45 Shah SS, Thompson J, Goldstraw P Results of operation without adjuvant therapy in the treatment of small cell lung cancer Ann Thorac Surg 1992;54:498–501 112 / Advanced Therapy in Thoracic Surgery 46 Prager RL, Foster JM, Hainsworth JD, et al The feasibility of adjuvant surgery in limited-stage small cell carcinoma: a prospective evaluation Ann Thorac Surg 1984;38:622–7 of a stage oriented multimodality treatment including surgery for selected subgroups of limited disease small cell lung cancer [abstract 235] Lung Cancer 1997;18 Suppl 1:61 47 Williams CJ, McMillan I, Lea R, et al Surgery after initial chemotherapy for localized small cell carcinoma of the lung J Clin Oncol 1987;5:1579–88 55 Yamada K, Saijo N, Kojima A, et al A retrospective analysis of patients receiving surgery after chemotherapy for small cell lung cancer Jpn J Clin Oncol 1991;21:39–45 48 Johnson DH, Einhorn LH, Mandelbaum I, et al Post chemotherapy resection of residual tumor in limited stage small cell lung cancer Chest 1987;92:241–6 56 Muller LC, Salzer GM, Huber H, et al Multi modal therapy of small cell lung cancer in TNM stages I–IIIa Ann Thorac Surg 1992;54:493–7 49 Baker RR, Ettinger DS, Ruckdeschel JD, et al The role of surgery in the management of selected patients with small cell carcinoma of the lung J Clin Oncol 1987;5:697–702 57 Shepherd FA Induction chemotherapy for locally advanced non-small cell lung cancer Ann Thorac Surg 1993;55:1585–92 50 Shepherd FA, Ginsberg RJ, Patterson GA, et al A prospective study of adjuvant surgical resection after chemotherapy for limited small cell lung cancer J Thorac Cardiovasc Surg 1989;97:177–86 58 Lad T, Piantadosi S, Thomas P, et al A prospective randomized trial to determine the benefit of surgical resection of residual disease following response of small cell lung cancer to combination chemotherapy Chest 1994;106(6 Suppl):3205–35 51 Benfield GFA, Matthews HR, Watson DCT, et al Chemotherapy plus adjuvant surgery for local small cell lung cancer Eur J Surg Oncol 1989;15:341–4 52 Zatopek N, Holoye P, Ellerbroek NA, et al Resectability of small cell lung cancer following induction chemotherapy in patients with limited disease (stage II–IIIb) Am J Clin Oncol 1991;14:427–32 53 Hara N, Ohta M, Ichinose Y, et al Influence of surgical resection before and after chemotherapy on survival in small cell lung cancer J Surg Oncol 1991;47:53–61 54 Eberhardt W, Wilke H, Stamatis G, et al Preliminary results 59 Shepherd FA, Ginsberg RJ, Haddad R, et al Importance of clinical staging in limited small cell lung cancer: a valuable system to separate prognostic subgroups J Clin Oncol 1993;8:1592–7 60 Shepherd FA, Ginsberg RJ, Patterson GA, et al Is there ever a role for salvage operations in limited small cell lung cancer? J Thorac Cardiovasc Surg 1991;101:196–200 61 Mangum MD, Greco FA, Hainsworth JD, et al Combined small cell and non-small cell lung cancer J Clin Oncol 1989;7:607–12 CHAPTER GENE THERAPY AND THORACIC SURGERY ROBERT I GARVER JR, MD Gene Therapy Basics Gene therapy can be broadly defined as the administration of nucleic acids that direct the production of a new protein within targeted cells By this definition, oligonucleotide therapeutics are not considered gene therapy since these short deoxyribonucleic acid (DNA) sequences not, themselves, direct new protein production In addition, lytic viruses that only contain viral genes and function as cytolytic therapy are not considered gene therapy for the discussion here Specific proteins have been identified that play a critical role in the initiation or regulation of many clinical entities affecting the thorax Since gene therapy has the potential for modifying proteins critical to a given disease state, the rationale for developing this modality is intuitively obvious As technologies developed in the past 10 to 15 years enabled a relatively large number of basic “proof of concept” gene therapy studies in preclinical models, many proponents of gene therapy made overreaching predictions of success in the clinical utility of present-day gene therapy It is now widely appreciated that gene therapy has not yet fulfilled these prophecies of rapid success, owing largely to the limitations of current gene-delivery technologies This chapter endeavors to achieve two specific objectives: (1) to provide an understanding of the most common gene therapy technologies, with some appreciation for the limitations that need to be overcome for improved efficacy, and (2) to review specific gene therapy approaches directed toward clinical problems facing the thoracic surgeon, including lung cancer, mesothelioma, and lung transplantation Choice and Engineering of the Therapeutic Gene Although messenger ribonucleic acid (RNA) has been used as the nucleic acid in a handful of preclinical gene therapy studies, the vast majority of gene therapy strategies employ the administration of DNA The primary DNA components required for the production of the new protein within the host cells include the transcription regulatory sequence (also known as the promoter) and the contiguous coding sequence, a combination variably designated as the transgene, expression cassette, or therapeutic gene (Figure 9-1) Several commonly used transcription regulatory sequences continuously direct relatively high levels of coding sequence transcription Transgene FIGURE 9-1 Transgene components The typical transgene employed for gene therapy is a deoxyribonucleic acid containing a promoter (transcription regulatory sequence) that directs the production of transcripts from the contiguous coding sequence Variations in types of promoters and coding sequence options are indicated in the figure text 113 114 / Advanced Therapy in Thoracic Surgery and are commonly referred to as constitutive promoters It is also possible, depending on the host cell target, to select a transcription regulatory sequence that will only be active in specific tissues such as hepatocytes or prostate cells The selection of such tissue-specific regulatory sequences obviously can be exploited as a means of targeting the new protein production to specific sites or tissues, a strategy sometimes referred to as transcription targeting Almost any coding sequence can be used in a gene therapy context, but experience over the past decade has defined several different thematic approaches (Table 9-1) The initial gene therapy approaches focused primarily on protein replacement/augmentation for heritable protein deficiencies such as ␣1-antitrypsin deficiency or cystic fibrosis More recently, the administration of transgenes encoding for angiogenic factors that stimulate new vasculature (eg, VEGF) has received significant attention based on potential efficacy observed in small numbers of patients Gene therapy approaches for neoplastic diseases relevant to thoracic surgical practice have spawned several other strategies that seek to destroy the tumor cells, directly or indirectly Direct antineoplastic genetic therapy approaches include toxin therapies in which the cancer cells are modified to produce a toxin (eg, diphtheria toxin) or a protein that converts a prodrug into a toxin (herpes simplex virus thymidine kinase [HSVTK]) Another direct antineoplastic strategy is the production of a protein that can dominantly suppress the effects of mutated oncogenes/tumor suppressor genes that perpetuate the neoplastic phenotype (eg, the introduction of wild-type TP53 into neoplastic cells with mutated or deleted TP53) Indirect antineoplastic strategies include the introduction of genes that direct the production of immunomodulatory agents with the aim of increasing the immune response directed against the neoplastic cells (eg, granulocyte-macrophage colony–stimulating factor) Standard genetic engineering technologies have been exploited to further improve the native coding sequences For example, fusion genes have been made so that the protein produced in transduced cells may be bifunctional, or targeted to a specific cellular compartment The portion of the gene coding for an enzyme active site can be mutated to code for “superenzymes” that are more efficient than the normal gene product Vectors The fundamental requirement for any gene therapy strategy is a delivery system, that is, a vector, that effectively delivers the therapeutic nucleic acid The vectors can be used to facilitate gene delivery in two contexts The first approach, ex vivo gene therapy, refers to a process wherein the target tissue is removed from the individual, TABLE 9-1 Thematic Gene Therapy Approaches Theme Common Targets Coding Sequence Example Protein augmentation Direct toxins Indirect toxins Heritable protein deficiencies Neoplasia Neoplasia Dominant suppression Immunopotentiation Neoplasia Neoplasia Angiogenesis Vascular disease, neoplasia Neoplasia Radiosensitizers ␣1-Antitrypsin Diphtheria toxin A Herpes simplex virus thymidine kinase (HSVTK) TP53 Granulocyte-macrophage colony–stimulating factor VEGF Cytosine deaminase exposed to the gene therapy vector in a tissue culture context, and at some point thereafter reintroduced into the host Ex vivo gene therapy can be accomplished by every gene therapy vector system and has been shown to be quite safe This gene therapy paradigm is obviously limited to those clinical situations in which the genetically modified cells are replaced within the host so as to direct an immune response or produce a deficient protein The second gene delivery approach is in vivo gene therapy, which refers to the administration of the gene therapy vector directly into the host/patient As is intuitively obvious, the vector requirements here are more stringent than in ex vivo gene therapy, because vector toxicity, host cell inactivation of the vector, and achievement of therapeutically meaningful delivery of the vector and its gene to the targeted tissue are all important barriers to success The ideal gene therapy vector is one that efficiently transfers the functional, therapeutic DNA into all cells of a target tissue following intravenous administration, an ideal that can be designated as a targetable-injectable vector This targetable-injectable vector system is also nontoxic and easily manufactured and stored In the very brief review of currently available vector systems, the reader will appreciate that the ideal vector has not yet been developed, and the significant limitations of available vector systems is the greatest impediment to clinical efficacy attained by gene therapy viral vector systems A variety of viruses have been modified for gene therapy applications (Figure 9-2) In most cases portions of the viral genome have been deleted so as to render the virus replication defective as well as provide space for the addition of the therapeutic transgene At the time of this writing, three viral vector systems have played a dominant role in both preclinical and in human clinical trials: retroviruses, adenoviruses, and adeno-associated viruses (Table 9-2) 116 / Advanced Therapy in Thoracic Surgery article by Gao and colleagues for a recent, comprehensive review of AAV vectors.3) In spite of these limitations, AAVs have recently been shown to have potential utility in hemophilia nonviral vector systems A large number of nonviral vector systems have been employed for basic studies of gene transfer (see Figure 16–2), but the majority of these methods are too toxic or impractical for clinical applications The clinically relevant methods use one or more compounds that condense the DNA and facilitate target cell entry (For a comprehensive review of nonviral vectors, see Nishikawa and Huang’s article.4) Cationic lipids have been the most widely used class of nonviral vectors These positively charged lipids form a complex with the negatively charged DNA to condense the DNA and serve to mask the negative charges that otherwise repel the DNA from cell membranes that are also slightly negative in charge The lipids interact with the cell membranes by a receptorindependent mechanism, resulting in cytoplasmic entry by endocytosis Cationic lipids have been combined with other condensing agents as well as targeting moieties as a means of improving efficacy and attempting to target the delivery to specific cell types The advantages of cationic lipids over the viral vectors include (1) the elimination of many biohazard concerns associated with recombinant virus systems, and (2) the potentially greater uniformity, longer shelf-life, and easier storage than the viral agents However, the central limitation of the lipid-based vectors is the markedly lower gene-transduction efficiency compared with that of the viral systems, in part the consequence of host cell destruction of the therapeutic DNA that gains entry into the cytoplasm by receptorindependent pathways Some specific formulations have been developed that can improve the efficiency, but a large gap in efficiency remains between cationic lipids and viral vectors practical implications of the limitations posed by available gene therapy vector systems In the context of pathophysiologic states addressed by thoracic surgeons, the shortcomings of currently available vectors both limit the utility of intrathoracic gene therapy and dictate the means of administration All intrathoracic gene therapy strategies have required direct, local administration of the vector at the target For example, the TP53 gene therapy for nonsmall cell lung cancer (NSCLC) has used intratumoral injections containing the vectors with the wild-type TP53 expression cassette This means of vector administration results in limited distribution of the vector within the target tissue site, although efficacy can be better than expected owing to “bystander effects.” Bystander Effects If one accepts the premise that gene therapy works by modifying the genetic makeup of cells one cell at a time, then the corollary of this expectation is that the majority of cells within a target tissue must be transduced with the therapeutic gene for efficacy In a variety of contexts, preclinical animal models have shown that some gene therapy strategies overcome this apparent limitation of gene therapy by a bystander effect The bystander effect simply refers to the transduced cells exerting therapeutically desirable effects on surrounding, nontransduced cells that have not been genetically modified (Figure 9-3) The existence of the bystander effect was first described with the HSVTK system, in which cells modified to express the viral thymidine kinase convert the antiviral drug ganciclovir into its toxic form, which subsequently kills the cell In preclinical studies it was found that the proportion of cells killed greatly exceeded the proportion of cells actually modified to contain the HSVTK protein Mixing experiments, in which HSVTK-containing cells were mixed with naive cells, confirmed that ganciclovir sensitivity had apparently spread to neighboring cells that had not been genetically modified It was subsequently shown that the HSVTK bystander effect was largely the consequence of the modified ganciclovir produced within the genetically modified cells disseminating to neighboring cells by intercellular junctional communications.5 Other bystander effects for other transgenes have been identified, although the mechanisms are not all as completely understood New Gene Recipient FIGURE 9-3 Bystander effect Shown is a schematic representation of nine cells, but only the cell in the center of this group has received the intact viral transgene represented by the bar in the nucleus However, all of the neighboring cells are killed with the single genetically modified cell as a consequence of the bystander effect Several bystander effects have been described that work by different mechanisms Gene Therapy and Thoracic Surgery / 117 Summary The initial gene therapy experience has identified genetic strategies that can be effective in modifying target tissues in a clinically meaningful way, based on preclinical animal models These “proof of principle” studies have helped identify gene products that play essential roles in a variety of pathophysiologic states It should be clear from the previous sections that the greatest barrier to broad, clinical use of gene therapy for any clinical situation, including intrathoracic diseases, is the development of better vector systems Incremental improvements have been made in the extant vector systems, such as the development of some rudimentary targeting methodologies that can direct the vector away from some tissues that may sustain vector damage (eg, hepatocytes) and toward the desired target However, it can be argued that the vector field has not produced any vector systems that are not simply modifications of existing vectors in more than a decade Once the vector barrier is overcome, gene therapy will become a mainstream therapeutic modality—but for the present, it remains one with narrow applications that can be addressed with the limited vector technology we have today Intrathoracic Gene Therapy Relevant to Thoracic Surgical Problems The remainder of this chapter highlights selected gene therapy strategies that have been most extensively studied for intrathoracic conditions encountered by the thoracic surgeon Lung cancer and mesothelioma are the two conditions relevant here that have been subjected to the majority of gene therapy investigations, although a few studies have addressed aspects of lung transplantation Preclinical Studies of Lung Cancer Gene Therapy There are two overriding rationales for the interest in exploring the feasibility and efficacy of gene therapy for lung cancer First, novel therapy development is highly appropriate for this common neoplasm that has an unacceptably low disease-free survival Second, the past two decades have led to the identification of common somatic mutations that have been shown to play a key role in the initiation and perpetuation of the transformed respiratory epithelium that comprises lung cancer The identification of these mutations has provided targets for gene therapy, and, in fact, some of the gene therapy experiments have demonstrated the critical role that some mutations play in perpetuation of the transformed state Table 9-3 lists strategies and specific transgenes that have been employed in preclinical gene therapy studies for lung cancer Given the propensity for small cell lung cancer (SCLC) to undergo widespread metastasis and the current lack of a targetable-injectable vector system, the interest in pursuing gene therapy for this category of lung cancer has been relatively limited The efforts for SCLC have been primarily restricted to using tissuespecific promoters to direct HSVTK expression within the neoplastic cells There have been no clinical trials of gene therapy for SCLC The preclinical studies of gene therapy listed in Table 9-3 illustrate that considerably more effort has been expended in exploring gene therapy for NSCLC Various HSVTK strategies have been employed that use tissuespecific promoters or fusion proteins, for example Although NSCLC has not been a favorite target of immunotherapy studies, several studies have employed cytokines, immunogenic proteins (MDA7), or cofactors that promote immune responses Radiosensitization and antiangiogenesis strategies have also been exploited in a limited number of studies As Table 16-3 shows, the largest effort has been directed toward the addition of genes encoding proteins that counteract a variety of oncogenes, antioncogenes, or other proteins that are essential in maintaining the neoplastic phenotype, a process that is broadly defined here as dominant suppression In most of these studies, the successful production of the transgene protein leads to the death of the neoplastic cell TABLE 9-3 Examples of Preclinical Gene Therapy Strategies for Lung Cancer Cancer Gene Therapy Strategy Example Small cell lung cancer Indirect toxin Nonsmall cell lung cancer Indirect toxin Immunopotentiation Dominant suppression Radiosensitizer Angiogenesis GRP = ; MYC-MAX = GRP promoter-directed HSVTK 26 Neuron-specific, enolase-directed HSVTK 27 MYC-MAX-directed HSVTK 28 Multiple HSVTK 29 HGPRT 30 IL2 31 IL1/IL3 32 CD4L33 MDA7 34 TP53 10 p16INK4a35 RB2/p13036 k-ras ribozyme37 p2738 cyclin D antisense39 E1A40 c-erb2 antisense41 IGFB-342 Na+/I+43 flt–receptor decoy 44 118 / Advanced Therapy in Thoracic Surgery Clinical Studies of Lung Cancer The tumor suppressor (antioncogene) gene TP53 encodes a protein that serves as a critical transcriptional regulator of many other genes that modulate cell growth/division and apoptosis (as reviewed in Malkin’s article6) One of the most important TP53 functions relevant to cancer therapy is its function as a genomic quality-control monitor, whereby damaged DNA is detected early in the course of the cell cycle Normally functioning TP53 halts the progression of the cell cycle in those cells with damaged DNA and initiates either a process of DNA repair or the onset of apoptosis Since many chemotherapies, as well as radiotherapy, act by inducing DNA damage in the malignant cells, those cells with mutated or absent TP53 protein might be expected to demonstrate resistance to the therapy as they continue to complete cell cycles in the absence of the TP53 checkpoint This expectation has been confirmed experimentally and has led to a broad interest in the development of therapies that can compensate for the loss of TP53 function Not surprisingly, gene therapy has been investigated as one means of correcting the somatic mutations of TP53 in neoplastic cells In the context of intrathoracic disease, NSCLC has been most extensively studied in both preclinical and clinical studies of TP53 gene therapy Since neoplastic cells have multiple somatic mutations in addition to those associated with TP53, it was not intuitively obvious that the correction of the TP53 protein alone by the addition of a wild-type TP53 gene would be sufficient to change the cell phenotype However, extensive experimentation with multiple neoplastic cell types, including NSCLC, has firmly established that addition of wild-type TP53 into neoplastic cells with defective/absent TP53 generally induces those cells to undergo apoptotic cell death.7 In other words, these experiments showed that it was not necessary to address the multiple other mutations in oncogenes and other growth regulatory genes that are commonly present in concert with TP53 mutations for TP53 gene therapy to trigger neoplastic cell death Since approximately 50% of NSCLCs contain a defective or absent p53 gene product, Dr Jack Roth and colleagues pioneered studies that examined the effects of transducing wild-type TP53 genes into NSCLC with defective or absent TP53 Initial studies established that NSCLC cell lines with mutated or deleted TP53—but not those with wild-type TP53—were killed by the addition of the normal TP53 gene Other in vitro studies by several groups have also shown that TP53 gene therapy can also function to both chemosensitize and radiosensitize NSCLC cells that are defective in TP53.9 However, many expected that TP53 gene therapy was little more than an in vitro laboratory phenomenon, where condi- tions allowed a large majority of the cells to receive the wild-type TP53 gene Since there was no apparent mechanism for a TP53 bystander effect, it was not clear that TP53 gene therapy would be efficacious in vivo, where only a minority of cells would receive the new gene because of the current vector limitations Importantly, subsequent animal studies established that the intratumoral administration of wild-type TP53 into engrafted NSCLC with mutant/absent TP53 by either retroviral or adenoviral vectors resulted in a marked reduction in tumor nodule growth.10 The preclinical efficacy in the tumor nodules could only be explained by some type of bystander effect There is some data suggesting that TP53 gene therapy may exert a bystander effect via antiangiogenic effects, but this is not yet completely understood.11,12 The success of the preclinical studies has been followed by an initial phase I clinical study in which wild-type TP53 carried within an adenoviral vector was administered via intratumoral injection into inoperable NSCLC with mutated/absent TP53 In this doseescalation trial that included 25 evaluable patients, 23 of 25 received multiple intratumoral injections with minimal toxicity Two of 25 patients had a partial response (PR), 16 of 25 had stable disease over to 14 months, and the remainder progressed Toxicity associated with the gene therapy was minimal A subsequent phase I trial by the same group assessed the safety of using adenoviral-mediated TP53 gene therapy in conjunction with chemotherapy In this trial 24 patients received cisplatin, followed days later by an intratumoral administration of TP53 Two of 24 patients had a PR, and 17 of 24 had stable disease; again, toxicity was minimal.14 A phase II trial by a different group also examined adenoviral-mediated TP53 gene therapy in combination with chemotherapy In this trial 25 patients received an intratumoral TP53 gene in combination with one of two chemotherapy regimens (carboplatin plus paclitaxel, or cisplatin plus vinorelbine) given to patients with advanced-stage disease Response rates and median survivals in patients receiving either chemotherapy regimen with the TP53 gene therapy were not significantly improved relative to the controls who received the chemotherapy alone.15 A second phase II trial has been reported by the Swisher and colleagues in abstract form that examined TP53 gene therapy in combination with radiotherapy.16 In this trial, subjects receiving radiotherapy concomitantly received intratumoral injections of Ad-p53 on days 1, 18, and 32 There were 13 evaluable patients: of 13 had a complete response and of 13 a PR, but 19% of the patients also experienced grade 3/4 toxicities It is worth noting here that one small, earlier phase I study examined the safety of administering a recombi- Gene Therapy and Thoracic Surgery / 119 nant adenovirus with a ␤-galactosidase gene that functions as a marker without any known therapeutic effect into NSCLC 17 In this trial of six patients, the virus administration was well tolerated and, surprisingly, four of six patients had PRs in the treated tumors This result raises a question about the mechanism responsible for the responses seen in some of the adenovirus-p53 trials that may involve effects related to the adenoviral vector as well as the p53 gene product resulting from the successful gene transfer in the treated lung cancers In summary, TP53 gene therapy has certainly substantiated the importance of mutated TP53 in the maintenance of the neoplastic phenotype Since many carcinomas contain a multitude of somatic mutations in genes relevant to cell growth, it was particularly noteworthy that the preclinical studies of TP53 gene therapy have identified mutant TP53 as a key target for future therapies—whether they be gene therapy or other modalities The limited clinical studies have generally shown that the adenoviral delivery of wild-type TP53 is well tolerated, although the studies of concomitant radiotherapy and Ad-p53 did reveal significant toxicity that might temper further increases in the amount of gene therapy vector administered The efficacy suggested by these early studies of very few patients has been quite modest, and certainly the data not yet support the widespread use of TP53 gene therapy in NSCLC However, as pointed out in earlier sections, it seems highly probable that the development of better vector systems could dramatically improve the efficacy of TP53 gene therapy for NSCLC, as well as reducing toxicity associated with the adenoviral vector system It should also be noted that approximately 50% of NSCLCs involve wild-type TP53 and are therefore not expected to derive any benefit from TP53 gene therapy, no matter how ideal a future vector system may be Mesothelioma Malignant mesothelioma of the pleural space is a relatively rare neoplasm that responds poorly to conventional therapy The team of Albelda and Kaiser has pioneered efforts to develop a gene therapy approach for this problematic neoplasm Their efforts have focused on a toxic gene therapy strategy employing an HSVTK-plusganciclovir system.18 As was briefly alluded to earlier, the HSVTK gene encodes for the viral thymidine kinase that, in and of itself, is not toxic to cells However, cells containing the HSVTK protein phosphorylate antiherpetic drugs such as ganciclovir into a nucleotide analog that kills the host cell The HSVTK-plus-ganciclovir system has been widely examined in preclinical and clinical gene therapy investigations for three reasons: (1) the protein encoded by the HSVTK gene is not, itself, toxic, so nonspecific gene transfer (into untargeted cells) does not lead to problems, (2) the drugs used in conjunction with HSVTK are already approved and available for human use, and (3) the toxicity is conferred only when ganciclovir is present, and in the event of undesirable toxicity, further problems could be greatly mitigated by simply withholding further ganciclovir infusions In preclinical studies of HSVTK gene therapy for mesothelioma, investigators employed an animal model in which human mesothelioma was engrafted into the peritoneal cavities of immunosuppressed mice or the pleural space of rats.19 Multiple intraperitoneal administrations of adenovirus with an HSVTK transgene resulted in significant reductions in tumor burden and survival advantage compared with those of controls These promising findings led to a phase I trial of adenoviral-mediated HSVTK gene therapy that was administered via thoracoscopic injection into the tumor mass The results of this phase I trial of 20 evaluable patients revealed some transient side effects, but only 11 of 20 had demonstrable gene transfer in spite of the direct thoracoscopic administration of the adenoviral vector into the tumor masses, a result that underscores the limitations of available vector systems.20 In this initial phase I report, investigators were unable to identify tumor reduction in any of the patients, although a minority of the patients appeared to have stable disease An extension of this trial is currently underway A novel alternative form of the HSVTK-plusganciclovir approach has been developed by Schwarzenberger and colleagues.21 In their strategy an ovarian carcinoma cell line designated PAI-STK is genetically modified to permanently express the HSVTK protein In preclinical animal studies of ovarian cancer as well as mesothelioma, it was observed that these PAI-STK cells preferentially adhere to the neoplastic cells within the host by an unclear mechanism, and subsequently lead to the killing of the neoplastic cells when ganciclovir is administered, presumably by the bystander mechanism The results of the first phase I trial of this strategy for mesothelioma have reported that the intrapleural infusion of the PAI-STK cells were well tolerated up to the maximal infused dose (3 ϫ 10 cells) 22 Some scintigraphic data suggested that the PAI-STK cells did home to areas of mesothelioma within the pleural space In this study there was no report of efficacy In summary, the current status of gene therapy for mesothelioma is similar to that for NSCLC, in that some small clinical trials have shown that the gene therapy approaches used have been relatively safe However, the currently published trials of gene therapy for mesothelioma have not shown any significant clinical efficacy The formidable challenge for mesothelioma gene therapy is the development of a gene-delivery system that will trans- 120 / Advanced Therapy in Thoracic Surgery duce the therapeutic gene into more than that portion of the tumor that resides at the edge of the pleural effusion space into which the vectors have been administered Lung Transplantation A small number of preclinical studies have started addressing lung allografts as targets of gene therapy These proof of principle investigations have sought to examine the feasibility of modifying allograft cells as a means of mitigating acute rejection, although other longer-term objectives may also be achieved by similar means One important aspect of lung allografts is the opportunity to infuse the vasculature or the bronchial tree in an isolated fashion for extended periods of time without the concern of vector effects beyond the lung, as would be the case in an intact host Rat lungs have been excised, and either naked plasmid DNA or cationic lipid complexes of plasmid containing marker genes have been instilled into the bronchial tree 23,24 In these studies successful gene transfer and subsequent gene expression were documented One study infused Brown Norway rat lungs with an adenoviral vector containing a transgene for CTLA-4Ig protein that greatly mitigates acute rejection in the rat allograft lung transplant model system.25 The lungs were subsequently engrafted into allogeneic Lewis rat recipients, and lungs that had been treated with the vector had a significant reduction in the histologic grade of rejection Certainly the handful of gene therapy studies directed toward lung transplantation have not clearly defined the optimal target genes and strategies necessary for a therapeutically meaningful intervention, but they are likely to stimulate further studies The author thanks Dr Paul Reynolds for his thoughtful review of this chapter This work was supported in part by a VA Merit Review awarded to Robert I Garver Jr References Hu WS, Pathak VK Design of retroviral vectors and helper cells for gene therapy Pharmacol Rev 2000;52:493–511 Hitt MM, Graham FL Adenovirus vectors for human gene therapy [review] Adv Virus Res 2000;55:479–505 Gao GP, Wilson JM, Wivel NA Production of recombinant adeno-associated virus Adv Virus Res 2000;55:529–43 Malkin D The role of p53 in human cancer [review] J Neurooncol 2001;51:231–43 Baker SJ, Markowitz S, Fearon ER, et al Suppression of human colorectal carcinoma cell growth by wild-type p53 Science 1990;249:912–5 Fujiwara T, Grimm EA, Mukhopadhyay T, et al A retroviral wild-type p53 expression vector penetrates human lung cancer spheroids and inhibits growth by inducing apoptosis Cancer Res 1993;53:4129–33 Fujiwara T, Grimm EA, Mukhopadhyay T, et al Induction of chemosensitivity in human lung cancer cells in vivo by adenovirus-mediated transfer of the wild-type p53 gene Cancer Res 1994;54:2287–91 10 Fujiwara T, Cai D, Georges RN, et al Therapeutic effect of a retroviral wild-type p53 expression vector in an orthotopic lung cancer model J Natl Cancer Inst 1994;86:1458–62 11 Rizk NP, Chang MY, Kouri CE, et al The evaluation of adenoviral p53-mediated bystander effect in gene therapy of cancer Cancer Gene Ther 1999;6:291–301 12 Nishiszaki M, Fujiwara T, Tanida T, et al Recombinant adenovirus expressing wild-type p53 is antiangiogenic: a proposed mechanism for bystander effect Clin Cancer Res 1999;5:1015–23 13 Swisher SG, Roth JA, Nemunaitis J, et al Adenovirusmediated p53 gene transfer in advanced non-small cell lung cancer J Natl Cancer Inst 1999;91:763–71 14 Nemunaitis J, Swisher SG, Timmons T, et al Adenovirusmediated p53 gene transfer in sequence with cisplatin to tumors of patients with non-small cell lung cancer J Clin Oncol 2000;18:609–22 15 Schuler M, Hermann R, DeGreve JL, et al Adenovirusmediated wild-type p53 gene transfer in patients receiving chemotherapy for advanced non-small cell lung cancer: results of a multicenter phase II study J Clin Oncol 2001;19:1750–8 16 Swisher S, Roth JA, Komaki R, et al A phase II trial of adenoviral mediated p53 gene transfer (IRPR/INGN 201) in conjunction with radiation therapy in patients with localized non-small cell lung cancer (NSCLC) [abstract] Proc Am Soc Clin Oncol 2000;19:461a 17 Tursz T, Cesne AL, Baldeyrou P, et al Phase I study of a recombinant adenovirus-mediated gene transfer in lung cancer patients J Natl Cancer Inst 1996;88:1857–63 Nishikawa M, Huang L Nonviral vectors in the new millennium: delivery barriers in gene transfer Hum Gene Ther 2001;12:861–70 18 Smythe WR, Hwang HC, Amin KM, et al Use of recombinant adenovirus to transfer the herpes simplex virus thymidine kinase (HSVtk) gene to thoracic neoplasms: an effective in vitro drug sensitization system Cancer Res 1994;54:2055–9 Mesnil M, Yamasaki H Bystander effect in herpes simplex virus–thymidine kinase/ganciclovir cancer gene therapy: role of gap-junctional intercellular communication Cancer Res 2000;60:3989–99 19 Smythe WR, Kaiser LR, Hwang HC, et al Successful adenovirus-mediated gene transfer in an in vivo model of human malignant mesothelioma Ann Thorac Surg 1994;57:1395–401 148 / Advanced Therapy in Thoracic Surgery swimming pools, beaches, and outdoor activities Adolescents and young adults are reluctant to undress in the presence of others In females, asymmetry of the breasts can further aggravate the issue Parents, who, themselves, may also have the anomaly, are especially protective of their children and not want them to endure the same unpleasant experiences they may have gone through After the surgery, in most patients attention is focused more on the esthetic correction rather than on the relief of clinical symptoms Timing of Surgery The younger the patient, the easier the correction is for the patient and for the surgeon Some argue that to years old is the best time for surgery; however, depending on the severity of the deformity, accompanying disorders, and clinical symptoms, it can be done earlier We disagree with the view that repair of pectus excavatum should be delayed because of the danger of developing “aquired Jeune’s syndrome”—a condition of arrested growth of the chest wall owing to overly radical cartilage removal.12 Surgery can be done at any age, but it has to be done well.13 Operative Indications and Surgical Correction The aim of surgical intervention is multifold: (1) to allow normal growth of the thoracic cage, (2) to prevent or treat pulmonary and cardiac dysfunction, and (3) to alleviate psychological problems Procedures described for surgical correction of pectus excavatum vary from the conservative, cosmetic, silicone implants to the radical, sternal “turnover” technique.13 The first step of “conventional” repair includes bilateral resection of the deformed costal cartilages, transverse osteotomy at the upper end of the sternal depression, and correction of the same by bending the sternum forward The second step, securing and maintaining the sternum in its corrected position, may use one of many recommended methods The techniques used for this purpose, based on the type of sternal support used, may be divided into two groups:procedures that not use special support and those that apply various types of sternal support The latter group may be further subdivided depending on whether external or internal support is employed Sternal support may be applied either anterior or posterior to the sternum using various plates, bars, and splints made of metal and other materials, bioabsorbable struts, Kirschner wires, autogenous bone and cartilage, and so on The most commonly used techniques involve the posterior support of the corrected deformity.14 There are some other techniques that not fall into these categories, such as the sternal turnover operation, various cosmetic silicone implants, and muscle flaps to camouflage the deformity, as well as “minimally invasive” techniques with or without endoscopy The long-term effectiveness of most has not yet been confirmed Our Recommended Operative Technique Over the years we have successfully used Marlex mesh (Bard, Inc, Cranston, RI) as a support to maintain the sternum in a corrected position.15 This technique, which we developed in the 1970s, employs the advantage of posterior support and does not carry the threat of dislodgment or require a second operation for its removal The mesh also allows tissue ingrowth and creates a solid and stable anterior chest wall With the patient under endotracheal anesthesia, a slightly upward convex transverse incision is made over the deformity in accordance with Langer’s lines In female patients special care is taken not to interfere with the growing breasts In severe cases in which the deformity involves the manubrium as well as the upper ribs, a midline vertical incision may be used, although it is less cosmetic The skin and the subcutaneous tissues are mobilized but not separated and are retracted in a single flap The dissection is extended up to the level at which the deformed cartilages start their depressed course Using a cautery, the pectoralis major muscles are detached bilaterally from the sternum and then retracted, exposing the costal cartilages The deformed cartilages (usually IV–VII) are resected subperichondrially on both sides, proportionally to the degree of their depression A shorter segment is resected from the upper cartilages, and progressively longer portions are removed as the procedure moves downward To ensure growth and regeneration, care is taken not to damage the growth plates at the junction of the cartilage and the bony rib Leaving the posterior lamina intact, a wedge-shaped transverse sternal osteotomy is made below the manubrium at the level at which the sternal depression begins The osteotomy is made in line with an intercostal space, rather than at the chondrosternal junction The xiphoid process is detached from the sternum The lower tip of the sternum is raised, the loose mediastinal tissue is dissected bluntly, and the intercostal bundles are bilaterally detached from the sternum close to its edges, leaving the mammary vessels intact The sternum is now bent forward at the line of the transverse sternotomy In the course of this manueuver, it is often necessary to break the posterior lamina To stabilize and maintain the sternum in this corrected position, a sheet of Marlex mesh is cut to the size of the previously existing depression and placed under the sternum The edges of the mesh are sutured tight, like a drum, to the distal ends of the divided costal cartilages and to the xiphoid with nonabsorbable heavy sutures (Figure 12-3) The substernal 150 / Advanced Therapy in Thoracic Surgery FIGURE 12-5 Repair of asymmetric pectus excavatum: unevenly resected cartilages, a transverse sternotomy, the sternum detached from the perichondrial connections and its rotation corrected, and the internal thoracic vessels left laterally intact Inset: Lateral view of a reversed figure-of-eight suture after the repair of pectus excavatum should not occur in ≥ 5% of patients.12 Recurrence should not be mistaken for residual deformity, which is usually caused by inadequate cartilage resection The lack of appropriate support after surgical correction and continued overgrowth of cartilages in connective tissue disorders can cause recurrence Redo operations are feasible and employ the same principles as the initial operation; however, they are much more difficult and time consuming There is no obvious correlation between the age at repair and the frequency of recurrence Innovative cosmetic correction of pectus excavatum with autologous adipose flaps (vs silicone prosthetic implants) during reduction mammoplasty has potential oncologic implications owing to the possibility of developing breast cancer outside the breast boundaries Flap atrophy may also occur.17 We not recommend the use of metal supports in the repair of pectus excavatum because of the possibility of migration and the potential for injury to the thoracic or even abdominal organs, and because of the necessity of removing these contraptions to 12 months after their implantation Chest pain and pleural or pericardial effusion may point to displacement or fracture of the support and indicate its urgent removal The possibility of heart chamber intrusion (primarily into the right ventricle) with thrombus formation should always be kept in mind and also may necessitate the establishment of a cardiopulmonary bypass.18 Positional asymmetry and disturbed growth of the female breasts may occur in the course of pectus repair if the surgeon misjudges the extent of mammary tissue in children, which can be more medial in girls with funnel chest When the skin incision is made, a safe distance of cm below the areola (in prepubertal girls) should be maintained in bow-shaped inframammary incisions.19 The extent of the deformity may necessitate a vertical incision; however, this is more prone to keloid formation “Crosseyed” nipples can be corrected by triangular skin plasty.13 Very rarely the repair of pectus excavatum can lead to thoracic outlet syndrome owing to the additional displacement of the ribs in patients with preexisting positional abnormalities of the first and second ribs Prior to pectus surgery, minor signs of neurovascular compression caused by latent thoracic outlet syndrome should be documented In addition, hyperabduction of the arm during surgery should be avoided.20 Pectus Carinatum Pectus carinatum is a protrusion deformity of the anterior chest wall with an abnormal prominence of the sternum and/or adjacent costal cartilages It is the second most common chest wall anomaly after pectus excavatum The proportion of occurrence between pectus carinatum and pectus excavatum ranges from 1:13 to 1:4 Pectus carinatum accounts for to 22% of all anterior chest wall deformities Males are affected two to four times more frequently than females.1,2 Among healthy school-age students, the condition is present in 0.06 to 1.7%.1,21 Most cases of pectus carinatum are sporadic; however, familial incidence has been reported in as many as 26% of cases.2 It can also be part of a syndrome or connective tissue disorder The basic etiologic mechanism is thought to be overgrowth of the costal cartilages, just as occurs in pectus excavatum, with secondary forward displacement of the sternum.22 Carinatum deformities may be divided into three main groups: (1) keel chest, (2) lateral pectus carinatum, and (3) pouter pigeon breast Iatrogenic pectus carina- Management of Chest Wall Deformities / 151 tum may be of traumatic or surgical origin.21 Patients may also have advanced congenital heart disease that causes right ventricle enlargement severe enough to create a carinatum deformity In a category by itself is secondary pectus carinatum owing to severe kyphosis deformity.22 Keel Chest: Classification Keel chest has two varieties Chondrosternal prominence is the most common variety of pectus carinatum and is characterized by forward displacement of the lower third of the sternal body, with maximum prominence at the sternoxiphoidal junction The condition has also been referred to as pyramidal chest, sternal kyphosis, chicken breast, sternum cuneiform, piriform chest, and oblique pigeon breast, among others The chest may also be barrel shaped (often seen in toddlers), with the sternum arching forward at its middle section In sternum elevatum, the sternoxiphoidal junction is “in line” with the sternal axis, and the maximal prominence is at the tip of the xiphoid process.14,22 The ossification pattern is normal in keel chest The angle of Louis (the angle between the manubrium and body of the sternum) approaches 180Њ The body habitus of most patients is usually asthenic The deformity is often associated with the bilateral depression of the lower costal cartilages, mistakenly identified by some as Harrison’s grooves These depressions can be fairly deep and significantly contribute to the reduction of thoracic capacity.21 In our experience keel chest was identified at around years of age in 75% of cases The next peak of identification was observed at to 11 years and was probably due to a period of accelerated growth In lateral radiographs the anteroposterior diameter of the chest is increased, the ribs seem to tear away from the sternum, and the retrosternal space is extended The elongated cardiac silhouette is positioned in the middle mediastinum.21,23 Lateral Pectus Carinatum Lateral pectus carinatum is characterized by marked unilateral protrusion of the costal cartilages, usually from the second rib down Often there is concomitant rotation of the sternum (30–45Њ) along its longitudinal axis toward the opposite side A less frequently encountered variety is the localized prominence of only two cartilages with minimal or no sternal involvement This condition is always asymmetric Clinical Features Pain from local trauma to the protruding sternum and discomfort during sleep in the prone position are the most frequent complaints with pectus carinatum Significant respiratory symptoms are rare; however, less severe symptoms, such as moderate dyspnea, fatigue, asthmatic signs, and nondescript chest pain, are present in about one-third of these patients Respiratory insufficiency associated with cor pulmonale may be seen in patients with a combination of severe kyphosis and pectus carinatum Cardiac symptoms are less common in patients with keel chest than in those with pectus excavatum The clinical symptoms are rare and may be due to decreased pulmonary reserve, caused by impaired respiratory movements of the thorax with increased residual air and reduced vital capacity The incidence of scoliosis has been reported in 15 to 37.8% of patients with pectus carinatum, with the single thoracic curve between the fourth and ninth vertebrae, with an average angle of 16Њ.2,10,24 Psychological Effects The psychological effects of pectus carinatum, in general, are more prevalent than are those of pectus excavatum Because of the protruding character of the deformity, it is more difficult to hide under clothing Depressions on both sides of the sternum, if present, further emphasize the protrusion In cases of lateral pectus carinatum, even a moderate prominence makes the chest appear unsightly To conceal the protrusion, patients hold themselves slightly bent, which leads to an abnormal posture and further aggravates the deformity Treatment Various nonoperative methods, such as physiotherapy, the use of plaster of paris, and external compression, are dismissed by the words of Howard: “The remedy for the deformity is operation Physiotherapy is useless without operation, and retaining apparatus is worse than useless.”1 We prefer to surgery before children reach school age to prevent psychological trauma and pathologic posture Also, at this age, it is easier to perform extensive surgical correction surgical correction of keel chest For the surgical correction of keel chest, a bow-shaped submammary skin incision is made After the skin and subcutaneous tissues have been mobilized, they are retracted cranially Deformed cartilages are exposed either one by one or by detaching and laterally retracting the pectoralis major muscle Subperichondrial resection of the deformed costal cartilages is then performed on both sides If the protrusion of the cartilages is asymmetric, it is corrected by uneven bilateral resections Inadequate resections may lead to residual deformity and 152 / Advanced Therapy in Thoracic Surgery unsatisfactory cosmetic results Resection of portions of the bony ribs is rarely necessary, even in advanced cases In chondrosternal prominence where there is angulation at the sternoxiphoidal junction, the xiphoid process is detached and a to cm length of the lower sternum is resected A transverse sternotomy is performed at the level of the beginning of the abnormal forward curve The sternum is bent at the level of the sternotomy and pressed posteriorly; it is thus brought into a corrected position (Figure 12-6) It is a good practice after correction of the anomaly to pull the skin edges temporarily together and observe carefully to see whether additional corrective steps need to be made before permanent closure is undertaken Unless the patient already has a chest tube, the substernal space is drained using a perforated vacuum drain through a separate stab incision through the inferior skin flap FIGURE 12-6 Keel chest repair: transverse sternotomy at the beginning of the forward curve, bilateral subperichondrial resection of the deformed cartilages, and the sternum shortened by resection The xiphoid process is reunited with the sternum Inset: Lateral view: A, anatomy of the deformity; B and C, steps of correction The xiphoid process and rectus muscle are then reattached to the caudal end of the sternum to further secure the sternum in its corrected position Care should be taken that the latter maneuver is done under tension to ensure traction upon the sternum by the rectus muscles via the xiphoid The edges of the pectoralis muscle are now united in front of the sternum to further secure its corrected position and to provide a smooth, soft contour to the anterior chest wall If there is no sternoxiphoidal forward angulation but the xiphoid itself is elevated (sternum elevatum), xiphoid detachment and sternum resection are omitted (Figure 12-7) The wound is then closed layer by layer A light compression dressing further secures the corrected position of the anterior chest wall FIGURE 12-7 Repair of pectus elevatum: bilateral subperichondrial resection of the deformed cartilages After a transverse sternotomy, the sternum is pushed down Inset: Lateral view: A, anatomy of the deformity; B and C, steps of correction Management of Chest Wall Deformities / 153 surgical correction of lateral pectus carinatum The operation for the repair of lateral pectus carinatum has to be tailored to the extent and location of the deformity; it may be very simple or quite extensive If the anomaly consists only of unilateral overgrowth of a few cartilages, the skin incision is made directly over them, the muscle fibers are separated, and the procedure is limited to subperichondrial removal of the unsightly protuberance It is advisable, however, to be radical rather than conservative and to resect the neighboring cartilages If the anomaly also involves the bony portion of the rib, one should not hesitate to remove the bony protrusions as well If the procedure necessitates more extensive resection of costal cartilages on one side, removal of a short segment of corresponding cartilages on the contralateral side is advised to prevent tilting of the sternum, which may cause recurrence of the anomaly If pectus carinatum is accompanied by kyphosis, the matter of operative indication and the surgery itself should be a combined undertaking of both a thoracic and an orthopedic surgeon Simultaneous operations on the anterior chest wall and the spine should be avoided Pouter Pigeon Breast Pouter pigeon breast is a rare congenital deformity of the chest characterized by a protrusion of the manubriosternal junction, the adjacent ribs, and premature sternal ossification It is considered to be the second most common type of pectus carinatum, although it is noticeably different in nature from keel chest and lateral pectus carinatum Most often it occurs as a single anomaly, but it also can be a part of syndromes such as Noonan’s and Turner’s.1,25,26 The condition is also known by the following pseudonyms, among others: arcuate pectus carinatum, chondromanubrial prominence with chondrosternal depression, Currarino-Silverman syndrome.1,2,25,26 In our experience the deformity was spread evenly between males and females.21 There also have been familial cases reported.2,23 clinical features The main clinical feature of pouter pigeon breast is the protrusion of the junction between the manubrium and the body of the sternum, with a reduction in the angle of Louis The adjacent costal cartilages, usually from II to V, also protrude Abnormal ossification of the manubr iosternal junction is always present (Figure 12-8A and B) Normally, manubriosternal synchondrosis exists throughout life and is replaced by synostosis only in 10% of the population All patients with pouter pigeon breast, regardless of age, have a completely ossified manubriosternal joint Fusion of the sutures between the four sternal segments (sternebrae) also occurs prematurely This abnormal ossification may happen as early as years of age and can be confirmed with conventional lateral radiographs 25,26 The sternum is slightly wider and thicker than normal In lateral view the anterior chest wall is Z-shaped The term angulated synostosis of the sternum may best describe the anatomic and morphologic peculiarities of this abnormality Depression of the lower third of the sternal body is present in about one-third of the patients (Figure 128C), and because of this the condition is frequently mistaken for pectus excavatum, despite being distinctly different in other aspects Protrusion of the manubrium often creates the illusion of mesosternal depression The condition is usually symmetric cardiac abnormalities Several cardiovascular abnormalities may coexist with premature sternal ossification, ventricular septal defect being the most common Presence of congenital cardiac disease in patients with pouter pigeon breast and abnormal ossification of the sternum has been estimated to be from 18 to 55%.2,23,25,26 This makes the search for occult cardiac lesions advisable in all patients with this deformity respiratory disorders Abnormal pulmonary function is uncommon, and if it occurs it is less severe in patients with pouter pigeon breast than in those with either pectus excavatum or classic keel chest However, patients with pouter pigeon breast have restricted compliance of the rib cage owing to ossification of the manubriosternal junction; such compliance is thought to be physiologically necessary for optimal respiratory function psychological effects Because of the appearance and particularly high location of pouter pigeon breast on the anterior chest wall, patients refuse to wear a deep décolletage Usually, an awareness of the deformity and the associated negative emotions materialize at around years of age, with full psychological impact at around 10 years of age classification Determination of the angle of Louis on the lateral chest radiograph allows the objective measurement of the deformity and also assists in the selection of the proper surgical technique (see Figure 12-8) The normal angle of Louis is between 175 and 145Њ When the angle reaches 130Њ (mild deformity), we recommend only follow-up once a year In patients with an angle of ≤ 130Њ, we Management of Chest Wall Deformities / 155 FIGURE 12-10 Full-blown Poland’s syndrome with the absence of the sternocostal part of the pectoralis major muscle, the absence of the pectoralis minor muscle, hypoplasia of the latissimus dorsi, aplasia of ribs III to V, and ipsilateral “mitten hand.” Reprinted with permission from the Society of Thoracic Surgeons.51 FIGURE 12-9 Repair of pouter pigeon breast with mesosternal depression: chiseled manubrial protrusion, wedge-shaped sternotomy of the angle of Louis, and linear sternotomy at the depressed site Marlex mesh underneath the sternum is stretched and sutured to the distal stumps of the resected costal cartilages The xiphoid is reattached Inset: Lateral view: A, anatomy of the deformity; B and C, steps of correction Poland’s Syndrome between the extent of the deformities of the hand, breast, and chest wall Poland’s syndrome is almost always unilateral, although a single bilateral case has been reported.29 The anomaly was first described in 1826 by L.M Lallemand and then in 1841 by Alfred Poland The estimated incidence of Poland’s syndrome is in 30,000 live births Males are affected more frequently than females by a ration of 3:1 or 2:1 The right side of the body is involved in 60 to 75% of cases.1,2,30 Poland’s syndrome is a rare congenital anomaly characterized by brachysyndactyly, hypoplasia or absence of the breast and/or nipple, hypoplasia of the subcutaneous tissue, absence of the costosternal portion of the pectoralis major muscle, absence of the pectoralis minor muscle, aplasia or deformity of the costal cartilages or ribs II to IV or III to V, and alopecia of the axillary and mammary regions Concisely, it could be defined as pectoral aplasia-dysdactylia syndrome The extent and degree of various components of the syndrome are variable, and rarely does one individual manifest all of its features (Figure 12-10) 1,2,27,28 There is no correlation Etiology Poland’s syndrome is a nongenetic congenital abnormality with a low risk of recurrence (< 1%) in the same family A report of Poland’s syndrome in one identical twin provides evidence of its sporadic nature.31 However, familial transmission has been reported in approximately 25 cases and could be due to an autosomal dominant gene with low penetrance.27,28,30 The pathogenesis of Poland’s syndrome remains unclear Currently, the dominant theory is the “subclavian artery blood supply disruption sequence.”32 A meso- 156 / Advanced Therapy in Thoracic Surgery dermal defect during the sixth and seventh weeks of gestation leads to hypoplasia of the subclavian artery or one of its branches which, in turn, results in the interruption of the embryonic blood supply The site and amount of obstruction determine the extent of the anomaly Hypoplasia of the internal thoracic artery causes the absence of the sternocostal portion of the pectoralis major muscle, whereas hypoplasia of branches of the brachial artery leads to hand abnormalities Clinical Features In all patients with Poland’s syndrome, the sternocostal attachment of the pectoralis major is absent, and in most cases the pectoralis minor is absent as well The absence of the pectoral muscles, however rarely, causes functional impairment In some cases the latissimus dorsi, external oblique, and serratus anterior muscles may also be affected Breast-involvement ranges from mild hypoplasia to complete absence (amastia) The nipple and areola are usually hypoplastic and elevated, lightly pigmented, or even absent (athelia) Supernumerary nipples may also be present In some cases the entire rib cage is normal, with only the pectoralis muscles absent; however, there is often an ipsilateral depression of the chest wall with hypoplasia of the ribs and cartilages Usually, ribs II to IV or III to V are involved, with the second rib being the least frequently involved Aplasia of the anterior portions of one to three ribs with more severe lateral depression may occur in up to 11% of patients.2,28 The sternum may rotate toward the involved side, thus forming an asymmetrical contralateral pectus carinatum.2 Dextrocardia in patients with left-sided Poland’s syndrome has been documented in 17 patients and was combined with rib defects, although it was not associated with other cardiovascular anomalies.33 Lung herniation occurs in 8% of the cases Conventional anteroposterior radiography usually demonstrates the unilateral hyperlucent lung.1,27,28 Hand involvement in Poland’s syndrome may vary from mild shortness of the middle phalanges with cutaneous webbing to a complete absence of the hand The reported incidence of hand anomalies in Poland’s syndrome has been reported from 2.5 up to 56% In turn, in patients with syndactyly, about 10% have Poland’s syndrome.2,34 It may occur that one family member shows isolated pectoral hypoplasia, which is also considered to be Poland’s syndrome, while another member may have the combined hand-pectoral deformity Cases without involvement of the hand are defined as “partial Poland’s sequence” and occur with greater frequency than does full-blown Poland’s syndrome.1,2,27,34,35 There is a well-known association between Poland’s syndrome and Möbius’ syndrome, a bilateral congenital facial nerve palsy with paralysis of the abductors of the eye It has been proposed that premature regression of the primitive trigeminal arteries might be the cause.32 In some patients with Poland’s syndrome, absence of the upper portion of the serratus anterior results from the obstruction of blood flow in the suprascapular arteries and leads to elevation and winging of the scapula (Sprengel’s deformity).32 Klippel-Feil syndrome may also accompany Poland’s syndrome.32 Klippel-Feil syndrome is characterized by a shortness of the neck resulting from fusion of the cervical vertebrae and abnormalities of the brainstem and cerebellum due to a delay in the development of the vertebral arteries There is also an association between aplasia of the pectoralis major muscle and renal anomalies (eg, unilateral renal agenesis or duplication of the urinary collecting system), which can be accompanied by renal hypertension.1 A relationship exists between congenital malformations and tumors Cases of Poland’s syndrome associated with leukemia, non-Hodgkin’s lymphoma, leiomyosarcoma, and cervical cancer, for example, have been reported Poland’s syndrome can also be associated with invasive ductal carcinoma in the hypoplastic breast Therefore all persons with Poland’s syndrome should be carefully monitored for early detection of cancer.1,36 Operative Indications Surgical intervention for Poland’s syndrome is indicated for the following reasons: (1) ipsilateral concave deformity of the chest wall and the possibility of its progression, (2) lack of adequate protection of the heart and lung, (3) paradoxic movement of the chest wall, and (4) aplasia or hypoplasia of the breast in female patients Anesthesia In patients with aplasia of ribs and lung hernia, unilateral ventilation of the opposite lung using a double-lumen endotracheal tube is recommended to prevent pulmonary injury.27 Epidural anesthesia is recommended during and after surgery with the end of the catheter at the level of the second or third thoracic vertebra.35 Treatment The surgical treatment of Poland’s syndrome, depending on the age and sex of the patient, may be carried out in one or two stages and involves stabilization and/or reconstruction of the chest wall with simultaneous augmenta- Management of Chest Wall Deformities / 157 tion mammoplasty in females The latter involves insertion of a breast prosthesis beneath an island pedicle musculocutaneous flap of the latissimus dorsi.27 Whereas in adults the correction should be done in one stage, in children the procedure is usually carried out in two stages: first the depression of the chest is corrected, then in adulthood latissimus dorsi muscle transposition and/or mammoplasty is carried out, when necessary Surgical repair involves the following: • When there is a large defect in the ribs and lung herniation, stabilization of the chest wall can be achieved by attaching split rib grafts taken subperiosteally from the unaffected side of the chest, using bony allografts from other parts of the body or a mesh patch to the edges of the defect (Figure 12-11) If a rib graft is used, the medial end of the graft is inserted into an opening created in the side of the sternum and then sutured Laterally the graft is attached to the freshened surface of the rib stumps If mesh is used, it should be stretched taut and sutured to the margins of the defect If both bony grafts and mesh are used, the mesh should be sutured to the rib grafts as well When the defect involves two ribs, it is possible to split the normal ribs above and below the defect and attach the newly created ends to the stumps of the aplastic ribs (Figure 12-12) In cases where ribs are fused at FIGURE 12-11 A, Poland’s syndrome with aplasia of ribs III to V and sternal rotation B, Split rib grafts are harvested from the contralateral side; they are secured medially into created sternal notches and laterally to the ends of the aplastic ribs Sternal rotation is corrected by an osteotomy and figure-of-eight suture C, Prosthetic mesh is sutured to edges of the defect and on top of rib grafts FIGURE 12-12 A, Poland’s syndrome with aplasia of the anterior portions of two ribs B, Ribs above and below the defect are split, and their ends reattached to the stumps of the aplastic ribs 158 / Advanced Therapy in Thoracic Surgery FIGURE 12-13 A, Repair of Poland’s syndrome with two ribs fused at their sternal ends B, Separation and reattachment of the lower rib to the sternum at the notch their sternal ends, reconstruction can be done by separating them and reattaching them to the sternum (Figure 12-13) • In cases of hypoplastic ribs with ipsilateral chest depression, correction should be accomplished by subperichondrial resection, along with Marlex mesh reinforcement • Sternal rotation, if present, should be corrected simultaneously with the rib correction and by transverse sternotomy and “reversed” figure-of-eight wire suture • Hypoplasia of the breast may be remedied using a prosthetic implant and/or musculocutaneous flaps • The loss of muscle mass and the anterior axillary fold can be corrected by transplantation of a latissimus dorsi musculocutaneous flap The status of the latissimus dorsi is of paramount importance and influences the surgical approach and results A hypoplastic latissimus dorsi muscle can be present with a normal-looking posterior axillary fold Clinical examination is therefore unreliable, and the anatomy of the muscle can only be accurately demonstrated by CT, magnetic resonance imaging, or mediolateral oblique mammography In cases involving a missing latissimus dorsi muscle, microsurgical transfer of the contralateral latissimus dorsi is an option.27,37,38 In cases involving a hypoplastic latissimus dorsi muscle, there have been reports of reconstruction using a free transfer of an upper gluteal flap or microvascular free abdominal muscle flap using internal thoracic vessels as recipient vessels.38 Complications To prevent displacement of the rib grafts, their medial ends should be embedded into an opening created in the side of the sternum and they should also be sutured to the prosthetic sheet above it After covering the rib defect with the autogenous fascia lata, slackening may occur over approximately months, causing the defect to reappear.1 Partial skin necrosis has also been reported when a hypoplastic latissimus dorsi was transplanted.37 The results of Poland’s syndrome repair are generally good We recommend a first follow-up examination months after surgery, following physical therapy to create a slight hypertrophy of transformed muscle flaps.35 Cleft Sternum Cleft sternum is a partial or complete separation of the lateral sternal bars and is also known as bifid sternum or sternal fissure It is caused by failed ventral midline fusion of the sternal bands, which normally occurs during the first months in the embryo Females with cleft sternum outnumber males, especially when the cleft is accompanied by a combination of supraumbilical raphe and facial hemangiomas.1,39,40 Clinical Features Cleft sternum presents as a concave defect of the sternum, which paradoxically deepens upon inspiration and bulges with expiration, coughing, or the Valsalva maneuver The shape of the defect varies from a narrow U to a broad V, the width of which may vary from to cm The pulsation of the heart is usually discernable through the thin and sometimes ulcerated skin Herniation of the lung may occur at the upper edge of the defect A midline, pigmented raphe reaching from the xiphoid process to the navel is common.41 Presence of an omphalocele or an umbilical hernia is frequent Intracardiac Management of Chest Wall Deformities / 159 anomalies such as ventricular septal defect or tetralogy of Fallot may also complicate sternal clefts An association with craniofacial hemangiomas is common Classification of the anomaly is based on some of the peculiar features, especially on the length of the fissure The correction of different varieties may require different surgical techniques There are four main types of sternal clefts Superior sternal cleft, the most common type of this malformation, involves the manubrium and the upper part of the body of the sternum and usually extends down to the level of the fourth intercostal space (Figure 12-14A) The position of the heart is normal, and the pericardium, pleura, and diaphragm are intact Subtotal sternal cleft involves the manubrium and most of the sternum, leaving only a narrow cartilaginous bridge (up to 15 mm) at the xiphoid process (Figure 12-14B) In cases of total sternal cleft, the sternal halves are completely separated (Figure 12-14C) This is the least common type of abnormality and may be mistaken for sternal agenesia Wide diastasis of the rectus abdominis muscle is common Inferior sternal cleft usually occurs in Cantrell pentalogy, which also includes an omphalocele or omphalocelelike abdominal defect, a crescent-shaped anterior diaphragmatic defect, and a hole in the pericardium, which allows pericardial-peritoneal communication (Figure 12-14D) Cantrell pentalogy is also often associated with various intracardiac anomalies, such as atrial or ventricular septal defects, tetralogy of Fallot, and left ventricular diverticulum.1,2,28 Clinical Symptoms Clinical symptoms of sternal clefts may be caused by abnormal changes in intrathoracic pressure, displacement of the heart and large vessels, and impairment of venous return Cyanosis, dyspnea, arrhythmia, and other circulatory difficulties may be present A chest wall defect can also lead to reduced air exchange and a loss of strength of cough Tracheal hemangioma can cause bleeding during endotracheal intubation.39–41 Diagnosis is easily established at birth Prenatal diagnosis is feasible in the last weeks of gestation by ultrasonography Establishment of diagnosis should initiate a thorough search for associated cardiovascular anomalies, as well as other midline structure malformations In children with fasciocutaneous vascular lesions, an angiographic examination of the vertebrobasilar system is recommended Congenital aortic abnormalities (aneurysm, coarctation) should be ruled out, especially FIGURE 12-14 Classification of the main types of sternal clefts A, Superior sternal cleft B, Subtotal sternal cleft C, Total sternal cleft D, Inferior sternal cleft 160 / Advanced Therapy in Thoracic Surgery in patients with hemangiomatosis and supraumbilical raphe On radiographs of the chest, superior mediastinal widening with an increased distance between sternal ends of the clavicles is noticeable Operative Indications Sternal clefts should be corrected for several reasons: (1) lack of bony protection of mediastinal structures makes the heart and great vessels vulnerable to trauma; (2) the appearance of a protruding heart is disturbing for both patients and parents; (3) enlargement of the defect, over time, worsens the appearance and makes it more difficult to correct; (4) the presence of a dermopericardial sinus may lead to pericardial infection; (5) paradoxic respiratory movements of the chest induce dyspnea and predispose recurrent respiratory infections; (6) impairment of the venous return affects cardiac function; and (7) umbilical hernia and rectus muscle diastases require correction and can be repaired simultaneously Surgical planning depends on the age of the patient, the type of the defect, and any accompanying anomalies of the heart By consensus, operative correction should be carried out during the neonatal period and certainly no later than months of age At this time the sternal halves may be sutured together without tension and the chest cavity will likely accommodate the thoracic viscera The maneuver of approximation of the ribs in the midline by applying gentle bilateral pressure on the chest (if the patient can endure it) can be used for “training” and ensure the surgeon that the repair will be well tolerated The presence of ulcerated and/or infected skin or a skin-to-pericardium sinus should hasten the time of surgical intervention.1,28 Simultaneous repair of cardiac and aortic malformations is feasible.43 At an older age, surgical repair is more difficult because the chest becomes rigid and may require more complex methods of repair The first successful operation for the anomaly was done by Burton in an 11-week-old child in 1943.44 Surgical repair is accomplished through a vertical midline incision Midline raphe or ulcerated skin, if present, should be excised The pericardium is dissected from the skin and sternal bands The periosteum is incised on the anterior aspect of the sternal halves, elevated, and then turned medial and inward (Figure 1215).45 The sternal halves are approximated and sutured together Notching of the sternal bars or a V-shaped sternotomy can ease their alignment 46 In older patients oblique or Z-shaped sliding chondrotomies adjacent to the sternum should be performed to further facilitate the approximation.45 If the cephalad diastasis is wide, it may require the detachment and mobilization of the stern- oclavicular junctions (Figure 12-16) The sternal bars are then united with nonabsorbable interrupted sutures passed through the remaining periosteum as well as the bone and reinforced with peristernal sutures.1,41 Uniting the sternothyroid, sternohyoid, and sternocleidomastoid muscles from both sides or switching the median sternal attachments of the sternocleidomastoid muscles prevents lung herniation at the base of the neck.41,47 In cases of subtotal sternal clefts, the cartilaginous bridge holding the halves apart should be resected before the bars are united FIGURE 12-15 Surgical correction of the superior sternal cleft: creation of the periosteal flaps, sliding chondrotomies, and notching of the sternal bars and midline wedge sternotomy for approximation of the sternal halves FIGURE 12-16 Repair of the superior sternal cleft: detachment at the sternoclavicular junction, suturing of the periosteal flaps, crossing and suturing of the medial attachments of the sternocleidomastoid muscles, and union of the sternal halves Management of Chest Wall Deformities / 161 In cases of total cleft sternum, the trimmed edges of the sternal halves are sutured together Diastasis of the rectus abdominis muscles, if present, should also be corrected.7 Reconstruction of the defect, especially if it is very wide or in adult patients, may require autologous bone graft or the application of a polytef or Marlex mesh patch or a titanium plate, for example.1,48 The first postoperative day is the most critical owing to the possibility of compression of the heart caused by acute reduction of the mediastinal space This makes careful monitoring of the patient’s cardiorespiratory status mandatory Epidural anesthesia is recommended after the operation Results and Complications Appropriate repair of sternal clefts should result in a solid anterior chest wall of normal shape Less satisfactory results such as the development of a fissure-like funnel chest deformity are rare and may require additional correction later on If the correction was not carried out high enough, herniation at the base of the neck may occur Torticollis can be prevented by the wearing of an orthopedic collar in the early postoperative period.41 Sternal Foramen Sternal foramen or congenital perforation of the sternum is a circular osseous defect (3–18 mm in diameter) usually located in the lower third of the sternal body and is caused by incomplete fusion of a single pair of sternal primordia The incidence of single, mesosternal midline foramen is about to 8% of the population Males are affected about twice as often as females.49 Because the anomaly may not be seen on routine radiographs, CT scanning is recommended to demonstrate the presence of this anomaly As a rule, the condition is asymptomatic A few lethal complications have been reported owing to secondary damage to the right ventricle or ascending aorta by a sternal biopsy or acupuncture needles used without a guard.50 In forensic investigations sternal foramen could serve as a trait peculiar to the individual in skeletal identification It also could be mistaken for a gunshot wound by the unaware or misdiagnosed as bone destroyed by osteomyelitis or carcinoma Shamberger RC Chest wall deformities In: Shields TW, LoCicero J III, Ponn RB, editors General thoracic surgery 5th ed Philadelphia: Lippincott Williams & Wilkins; 2000 p 535–61 Robicsek F, Sanger PW, Taylor FH, Thomas MJ The surgical treatment of chondrosternal prominence (pectus carinatum) J Thorac Cardiovasc Surg 1963;45:691–701 Welch KJ Satisfactory surgical correction of pectus excavatum deformity in children J Thorac Surg 1958;36:697–713 Chuang J-H, Wan Y-L Evaluation of pectus excavatum with repeated CT scans Pediatr Radiol 1995;25:654–6 Nakahara K, Ohno K, Monden Y, Kawashima Y An evaluation of outcome in patients with funnel chest by computed tomogram In: Wada J, Yokoyama M, editors Chest wall deformities and their operative treatment Tokyo: Ad Printing Inc.; 1990, 53–61 Shamberger RC Cardiopulmonary effects of anterior chest wall deformities Chest Surg Clin N Am 2000;10:245–52 Kamata S, Usui N, Sawai T, et al Pectus excavatum repair using costal cartilage graft for patients with tracheobronchomalacia J Pediatr Surg 2001;36;1650–2 Frick SL Scoliosis in children with anterior chest wall deformities Chest Surg Clin N Am 2000;10:427–36 10 Waters P, Welch K, Micheli LJ, Shamberger R, Hall JE Scoliosis in children with pectus excavatum and pectus carinatum J Pediatr Orthop 1989;9:551–6 11 Arn PH, Scherer LR, Haller A, Pyeritz RE Outcome of pectus excavatum in patients with Marfan syndrome and in the general population J Pediatr 1989;115:954–8 12 Haller JA Complications of surgery for pectus excavatum Chest Surg Clin N Am 2000;10:415–26 13 Robicsek F Surgical treatment of pectus excavatum Chest Surg Clin N Am 2000;10:277–96 14 Robicsek F, Fokin AA Surgical corrections of pectus excavatum and carinatum J Cardiovasc Surg 1999;40:725–31 15 Robicsek F Marlex mesh support for the correction of very severe and recurrent pectus excavatum Ann Thorac Surg 1978;26:80–3 16 Willekes CL, Backer CL, Mavroudis C A 26-year review of pectus deformity repairs, including simultaneous intracardiac repair Ann Thorac Surg 1999;67:511–8 17 Adams WP Discussion of article by Guimares J, Maia M, Monteiro E, Ferraro A Aesthetic correction of mild pectus excavatum with autologous tissue during mastopexy Plast Reconstr Surg 2001;108:757–62 References 18 Dalr ymple-Hay MJR, Calver A, Lea RE, Monro JL Migration of pectus excavatum correction bar into the left ventricle Eur J Cardiothorac Surg 1997;12:507–9 Ravitch MM Congenital deformities of the chest wall and their operative correction Philadelphia: WB Saunders Company; 1977 19 Hougaard K, Arendrup H Deformities of the female breasts after surgery for funnel chest Scand J Thorac Cardiovasc Surg 1983;17:171–4 162 / Advanced Therapy in Thoracic Surgery 20 Donders HPC, Geelan JAG Thoracic outlet syndrome after corrective surgery for pectus excavatum Neth J Surg 1988;40:20–2 36 Katz SC, Hazen A, Colen SR, Roses DF Poland’s syndrome and carcinoma of the breast: a case report Breast J 2001;7:56–9 21 Bairov GA, Fokin AA Keeled chest Vestn Khir Im II Grek 1983;130:89–94 37 Cochran JH Jr, Pauly TJ, Edstrom LE, Dibbell DG Hypoplasia of the latissimus dorsi muscle complicating breast reconstruction in Poland’s syndrome Ann Plast Surg 1981;6:402–4 22 Robicsek F Surgical treatment of pectus carinatum Chest Surg Clin N Am 2000;10:357–76 23 Fonkalsrud EW, Beanes S Surgical management of pectus carinatum: 30 years’ experience World J Surg 2001;25:898–903 24 Saxena AK, Willital GH Surgical repair of pectus carinatum Int Surg 1999;84:326–30 25 Currarino G, Silverman FN Premature obliteration of the sternal sutures and pigeon breast deformity Radiology 1958;79:532–40 26 Fokin AA Pouter pigeon breast Chest Surg Clin N Am 2000;10:377–91 38 Tvrdek M, Kletensky J, Svoboda S Aplasia of the breast— reconstruction using free TRAM flap Acta Chir Plast 2001;43:39–41 39 Eijgelaar A, Bijtel JH Congenital cleft sternum Thorax 1970;25:490–8 40 Gorlin RJ, Kantaputra P, Aughton DJ, Mulliken JB Marked female predilection in some syndromes associated with facial hemangiomas Am J Med Genet 1994;52:130–5 41 Fokin AA Cleft sternum and sternal foramen Chest Surg Clin N Am 2000;10:261–76 27 Urchel HC Jr Poland’s syndrome Chest Surg Clin N Am 2000;10:393–403 42 Pascual-Castroviejo I The association of extracranial and intracranial vascular malformations in children Can J Neurol Sci 1985;12:139–48 28 Landolfo K, Sabiston DC Jr Disorders of the sternum and the thoracic wall In: Sabiston DC, Spencer FC, editors Surgery of the chest 6th ed Philadelphia: WB Saunders Company; 1995 p 494–515 43 Bové T, Goldstein JP, Viart P, Duevaert RT Combined repair of upper sternal cleft and tetralogy of Fallot in an infant Ann Thorac Surg 1997;64:561–2 29 Karnak I, Tanyel FC, Tuncbilek E, et al Bilateral Poland anomaly Am J Med Genet 1998;75:505–7 30 Freire-Maia N, Chautard EA, Opitz JM, et al The Poland syndrome: clinical and genealogical data, dermatoglyphic analysis, and incidence Hum Hered 1973;23:97–104 31 Stevens DB, Fink BA, Prevel C Poland’s syndrome in one identical twin J Pediatr Orthop 2000;20:392–5 32 Bavinck JNB, Weaver DD Subclavian artery supply disruption sequence: hypothesis of a vascular etiology for Poland, Klippel-Feil, and Möbius anomalies Am J Med Genet 1986;23:903–18 44 Burton JF Method of correction of ectopia cordis Arch Surg 1947;54:79–84 45 Sabiston DC The surgical management of congenital bifid sternum with partial ectopia cordis J Thorac Surg 1958;35:118–22 46 Jewette TC, Butsch WL, Hug HR Congenital bifid sternum Surgery 1962;52:932–6 47 Daum R, Hecker WC Operative correction of total sternum bifida Thoraxchir Vask Chir 1964;12:333–9 48 Hazari A, Mercer N, Pawade A, et al Superior cleft sternum: construction with a titanium plate Plast Reconstr Surg 1998;101:167–70 33 Fraser FC, Teebi AS, Walsh S, Pinsky L Poland sequence with dextrocardia: which comes first? Am J Med Genet 1997;73:194–6 49 Cooper PD, Stewart JH, McCormick WF Development and morphology of the sternal foramen Am J Forensic Med Pathol 1988;9:342–7 34 Ireland DC, Takayama N, Flatt AE Poland’s syndrome J Bone Joint Surg Am 1976;58:52–8 50 Schratter M, Bijak M, Nissel H, et al Foramen sternale: minor anomaly—great significance Fortschr Rontgenstr 1997;166:69–71 35 Bairov GA, Fokin AA Surgical treatment of Poland’s syndrome in children Vestn Khir Im II Grek 1994;152:70–2 51 Fokin AA, Robicsek F Poland’s syndrome revisited Ann Thorac Surg 74:2218–25 CHAPTER 13 SURGICAL MANAGEMENT OF CONGENITAL LESIONS OF THE LUNG KAREN MICHIKO KLING, MD PAUL M COLOMBANI, MD Congenital lesions of the lung are a diverse collection of clinical entities that share characteristics due to their common embr yologic background The tracheobronchial tree develops between gestational weeks four and five with deepening of the laryngotracheal groove and separation from the primitive foregut Lung development occurs throughout fetal development and has four stages In the embryonic stage (weeks 0–7) the lung bud separates from the primitive foregut, and in the pseudoglandular phase (weeks 8–16) the remainder of the airways develop into the tracheobronchial tree Errors in mesodermal and endodermal embryogenesis and in lung bud migration lead to bronchogenic cysts, pulmonary sequestrations, congenital cystic adenomatoid malformations (CCAMs), epithelial foregut cysts, and foregut duplications Lung development is concluded with the canalicular and terminal sac stages, which involve development and growth of alveoli and their supporting vasculature; these occur between weeks 17 and 24 and between week 25 and term, respectively The exact time at which development goes awry determines exactly which anomaly or combination of anomalies will occur The overall occurrence of congenital lung anomalies is rare; there is no evidence of familial or ethnic preponderance although there is a slight predilection (1.3:1) for boys Most conditions are recognized within the first months of life and are limited to one hemithorax The most urgent clinical presentation is respiratory distress in the newborn period due to compression of adjacent functional lung, mediastinal shift, pulmonary hypoplasia, or airway obstruction Older children may present with recurrent infection, hemoptysis, or compression related phenomena such as dysphagia With the advent of more sophisticated and more prevalent imaging, anomalies are also found incidentally The widespread use of antenatal sonography makes this a common “presentation” and allows for early chromosomal analysis and echocardiogram to aid in antenatal care and decision making A multitude of studies can be obtained to aid in diagnosis; often the only one necessary is a chest roentgenogram or ultrasound that demonstrates a space-occupying lesion The imaging modalities chosen vary among institutions and are largely dependent on personal preferences, experience, and availability of technologists and specialized pediatric radiologists Ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI) more precisely define pulmonary involvement and vascular anatomy, but regardless of the specific diagnosis, most congenital lung anomalies require surgical resection and often anatomical considerations can most accurately be assessed and effectively addressed during surgery Therefore, additional invasive and costly imaging should be reserved for those cases in which the results may obviate operation or significantly alter the timing of operation or without which safety would be compromised For infants and children, noninvasive studies may require long periods of immobility that they may not tolerate without general anesthesia As will be addressed below, assisted ventilation with many of these lung lesions can be detrimental The surgical congenital lung anomalies include bronchogenic cysts, pulmonary sequestrations, congenital lobar emphysema (CLE), CCAMs, congenital chylothorax, pulmonary lymphangiectasis, pulmonary agenesis, and congenital pulmonary arteriovenous malformations Surgical resection is usually the treatment and can be limited to the defect itself but more commonly requires segmentectomy or lobectomy Resection is generally 163 164 / Advanced Therapy in Thoracic Surgery recommended as soon as thoracotomy and general anesthesia are deemed safe The urgency depends on the presence and severity of symptoms and the specific diagnosis Occasionally, incidental diagnoses in asymptomatic adults or those with preclusive medical comorbidities may warrant observation.1 Without comorbidities, thoracotomy and resection of these lesions are extremely well tolerated from a physiologic, pain, and recuperative perspective Outcome is dependent on associated pulmonary hypoplasia, pulmonary hypertension, fetal hydrops, cardiac compromise, renal anomalies, and syndromic defects Survival varies from more than 95% in children with isolated lesions to less that 10% in those with associated congenital complications or fetal hydrops Because of the dismal outcome for those with hydrops, an attempt to intervene through fetal surgery has become one of the newest surgical directives Bronchogenic Cyst Bronchogenic cysts arise from anomalous airway buds that contain nonfunctional pulmonary tissue (Figure 13-1) The cyst is lined with ciliated columnar or cuboidal cells with intervening mucous glands and the cyst wall contains both cartilage and smooth muscle Mucoid material is produced and accumulates within the cyst contributing to its growth Bronchogenic cysts represent 25% of the congenital bronchopulmonary anomalies and occur equally in male and female infants.2 There are no known associated syndromes or chromosomal abnormalities Cysts that develop during an embryological phase before the separation of bronchopulmonary and foregut elements may be intimately associated with the esophagus; cysts that occur during the pseudoglandular phase of proximal airway development are situated centrally within the parenchyma or about central air- FIGURE 13-1 Bronchogenic cyst: Ciliated columnar epithelium with smooth muscle cells in cyst wall 100ϫ magnification; hematoxylin/eosin stain ways Peripheral lesions develop during the canalicular phase of lung development in which alveoli are being formed Therefore, bronchogenic cysts occupy many locations (Figure 13-2) Cysts are usually, but not exclusively, situated in lower lobes, are single, and are unilateral; multiple or bilateral cysts may rarely occur Some report that parenchymal locations are the most common, accounting for up to 70% of bronchogenic cysts This is not universally accepted, however, and others report a predominance of mediastinal lesions, including cysts along the trachea, carina, proximal main stem bronchi, and paraesophageal area.3,4 In addition, bronchogenic cysts may be located in the neck, airway wall, chest wall, pericardium, pancreas, adrenal gland, and tongue Cysts are characteristically between one and ten centimeters long and gradually increase in size due to mucus production by the cyst epithelium Although there are almost always adherent fibrous bands connecting the cysts to adjacent tissue, cysts predominantly have no communication with the tracheobronchial tree, and this is the rule for extrathoracic cysts Rarely, especially with multiple, peripheral lesions, there will be some patency between cysts and other tracheobronchial structures.5 Two-thirds of children with bronchogenic cysts present early with symptoms while the other third have incidentally noted lesions and are typically older children or even adults More recently, bronchogenic cysts are being diagnosed on antenatal screening ultrasound The most common presenting symptom, which is infection, is seen in up to one-half of symptomatic patients Other complaints may be related to compression of the gastrointestinal tract and symptoms of dysphagia, mediastinal mass with airway compression, hemoptysis, or palpable mass Infants with multiple, peripheral cysts are FIGURE 13-2 Bronchogenic cyst: Possible anatomical locations ... MYC-MAX-directed HSVTK 28 Multiple HSVTK 29 HGPRT 30 IL2 31 IL1/IL3 32 CD4L 33 MDA7 34 TP 53 10 p16INK4a35 RB2/p 130 36 k-ras ribozyme37 p2 738 cyclin D antisense39 E1A40 c-erb2 antisense41 IGFB -3 4 2... colleagues in abstract form that examined TP 53 gene therapy in combination with radiotherapy.16 In this trial, subjects receiving radiotherapy concomitantly received intratumoral injections of Ad-p 53. .. the preclinical studies has been followed by an initial phase I clinical study in which wild-type TP 53 carried within an adenoviral vector was administered via intratumoral injection into inoperable