Thus, successful results in this group cannot necessarily be extrapolated to those who have previously shown very little or no evidence of progenitor mobilization. These results, although exciting, are incomplete, because no information was presented on subsequent engraftment after high-dose therapy. If a defective bone marrow microenvironment plays a role in poor mobilization, then it is at least theoretically possible that such patients might require more rather than fewer stem cells. The conflicting and somewhat disappointing results in nonmobilizing patients underscores how little is known about the biology of stem cell mobilization. In fact, the mechanism(s) of progenitor cell mobilization is unknown, including whether cytokines and chemotherapy act through the same or different pathways. Similarly, it is not known whether alternative mobilization strategies differentially impact on tumor cell mobilization, a variable that ultimately may prove to be more important than optimizing the number of stem cells harvested. Implicit in this recommendation was the probability that the blood was likely to be less contaminated with tumor cells than bone marrow. In fact, several studies in breast cancer and neuroblastoma patients show that the concentration of tumor cells is significantly less in blood stem cell collections. Chemotherapy can also result in tumor cell mobilization in patients with solid tumors. The clinical significance of administering tumor-contaminated stem cells is unclear. Gene marking studies in three different malignancies show that infused tumor cells contribute to relapse, 76,77 and 78 but no data suggest that they are the sole or even principal cause of recurrence. In patients with breast cancer, two studies have shown comparable outcomes in patients who did and did not have occult tumor in their stem cell product. Importantly, no obvious differences were noted between the two populations of patients with respect to stage, B symptoms, gender, bulky disease, remission status at harvest, or histologic evidence of marrow involvement. Although it can be argued that the pattern of relapse in previous sites of disease is evidence against the importance of infused tumor cells, it is also possible that infused tumor cells homed to sites of prior disease because of a favorable microenvironment. Because of the concomitant T-cell, natural killer cell, and monocyte depletion, there may be an increased risk of opportunistic infections that are otherwise rare in the autologous setting. In patients given unselected cells at the same institution, the risk of infection and disease were only 4. For patients with aggressive lymphomas, myeloma, and breast cancer, however, it seems clear that even substantial improvement in tumor purging will have little clinical benefit in the absence of better conditioning programs and more effective posttransplantation therapy. More recently, fludarabine, which is playing an increasingly important role in the treatment of low-grade B-cell lymphomas, has been identified as a stem cell toxin in some studies, 51,52,92 but not in others. After stem cell infusion, considerable controversy exists regarding the utility of hematopoietic growth factors. As a result, it seems likely that preparative programs for the two procedures eventually may radically diverge. Allogeneic conditioning programs have moved toward less acutely toxic, more intentionally immunosuppressive programs to facilitate donor engraftment. However, little evidence of progress in the construction of more effective autologous high-dose regimens has been seen over a period of 15 years, and it seems likely that the better outcomes reported more recently are more likely due to improvements in patient selection and supportive care. Alkylating agents have been the nucleus of most preparative programs, primarily because they demonstrate a disproportionate ratio of marrow to nonmarrow toxicity that is uniquely amenable to dose escalation followed by stem cell replacement. In addition, in vitro studies show a steep dose-response curve against tumor cell lines and minimal cross-resistance with other alkylating agents. As a result, minor degrees of drug resistance can theoretically be overcome by dose escalation or by the addition of other alkylating agents. Finally, analogous to other curative regimens, the combination of alkylating agents with nonoverlapping extramyeloid toxicity is theoretically possible with maintenance of near-maximum tolerated doses of each agent. It is not certain that radiation is superior to chemotherapy, however, even in the latter two diseases.
An isolated pleural effusion can be a manifestation of a peripheral lung carcinoma (usually adenocarcinoma), a mesothelioma or, rarely, a lesion from other sites. Diagnosis may be difficult; at times the primary tumor is not apparent even after thorocostomy and chest tube drainage. Electron microscopy may reveal ultrastructural features diagnostic of mesothelioma. In those with poor performance status or advanced age, a trial of tamoxifen or megestrol acetate is reasonable. In fit patients, a trial of chemotherapy (as discussed) for unknown primary carcinoma should be considered. Patients, therefore, may be diagnosed as having a neuroendocrine tumor or sarcoma. In these rare instances, a primary germ cell tumor (usually extragonadal) is present elsewhere and subsequently will be clinically apparent. The presence of a mediastinal, retroperitoneal, or testicular mass supports this possibility. Chromosomal analysis of tumor tissue may be diagnostic if a specific chromosome 12 abnormality is found. If affected patients have metastatic germ cell tumor with metastases of other histologies, the treatment of choice is cisplatin-based chemotherapy. Such patients appear to have a worse prognosis than do those with typical germ cell tumors, probably because the somatic cell tumors are less sensitive to chemotherapy. In our experience, detailed pathologic and molecular study occasionally has revealed a group of other specific diagnoses, including lymphomas, neuroendocrine tumors, germ cell tumors, sarcomas, and poorly differentiated carcinoma (otherwise not specified). Melanosomes or premelanosomes seen on electron micrographs have been considered diagnostic of melanoma but, on rare occasion, these structures are seen in other tumors. Some believe amelanotic melanomas do not always form premelanosomes, opening the question as to whether they really are melanomas. Immunoperoxidase panels also are useful in suggesting the diagnosis of melanoma (see Table 48-1). Of considerable interest is that in our original series of 220 patients with poorly differentiated carcinoma, 9 later were thought possibly to harbor amelanotic melanoma on the basis of immunoperoxidase stains or electron microscopy (or both). Generally, these patients responded well to cisplatin-based chemotherapy, and several had long-term survival, an unexpected result for "melanoma. In addition, the rare primary visceral melanoma should be considered (eye, adrenal, bowel, etc. Except in those patients who are discovered not to have melanoma but a specific tumor lineage requiring relatively specific therapy, the therapy for a questionable amelanotic melanoma is the same as that for carcinoma of unknown primary site presenting in a single site (local resection with or without radiation therapy). For patients with poorly differentiated tumor, including amelanotic melanoma, we also favor chemotherapy after local treatment. Many patients with poorly differentiated carcinoma have chemotherapy-responsive tumors, and complete responses and long-term survival have been documented for a minority of patients. Conversely, in the past, the even larger group of patients with well-differentiated adenocarcinoma has had relatively resistant tumors, with virtually no complete responses to chemotherapy and no long-term survivals. In the last several years, patients with other "favorable" factors have been recognized. Such patients, many managed with specific therapies, have a better prognosis than do those in the group as a whole. We have stressed that both pathologic and clinical factors now can define several patients with a better prognosis (Table 48-10). Although other unrecognized favorable features undoubtedly exist, apparently the prognosis of patients who do not fit into a favorable subset have a particularly poor prognosis, regardless of their initial light-microscopical diagnosis (well-differentiated adenocarcinoma or poorly differentiated carcinoma). Patients in this group recently have been treated with taxane-based chemotherapy, and the treatment does appear to improve the response rate (with some complete responses) and survival of these groups of patients with historically very poor prognoses. The degree of response seen in poorly differentiated neuroendocrine carcinoma also is noteworthy. Furthermore, the taxane-based chemotherapy appears as effective, with less toxicity, as cisplatin-based chemotherapy, even for those patients within favorable prognostic subsets who otherwise require chemotherapy. The one exception is patients with the extragonadal germ cell syndrome, for whom cisplatin-based therapy remains the treatment of choice. Further study of such patients with poor prognoses is necessary to continue to build on the progress seen with taxane-based combination chemotherapy.
Acral and Lentiginous Melanoma Due to functional concerns, there is a tendency to use smaller margins, perhaps accounting for the two- to fivefold higher incidence of local recurrence in this area. Melanoma of the head and neck usually occurs in an age group 10 years older than truncal and extremity melanoma. However, appropriate excision margins for Breslow depth should not be compromised solely on cosmetic bases. Since up to one-half degenerate into malignancy, the treatment of these lesions is warranted. The technique reduces scarring and may spare normal tissues by shaving involved tissues until a histologically negative margin. Some specialized centers have proposed the use of Mohs surgery in melanoma to minimize loss of normal tissue, especially in area such as the face, hands, and feet. Interesting differences exist between traditional surgical resection and micrographic surgery. Proponents of Mohs surgery claim that repeated frozen sectioning is accurate and saves normal tissues. Opponents cite the fact that satellite lesions may be missed using the Mohs technique and that pathologists do not generally examine the specimens. Critics also claim that frozen section is notoriously inaccurate for identification of melanoma. Treatment is usually administered with 6- to 9-MeV electron beams or 100- to 280-kilovolt (peak) x-rays using wide margins. This therapy may be appropriate for patients who cannot undergo or refuse surgery. Lesions can take up to 2 years to disappear after radiotherapy and the follow-up of available series remains short. Physicians have believed that a survival benefit exists after the early removal of nodes that are subclinically involved with tumor compared with removal once obvious nodal disease develops because the longer melanoma grows in the lymphatics, the more likely it is to metastasize systemically. After years of controversy surrounding the potential benefit of elective nodal dissection and numerous trials, it is ironic that, regardless of the conclusions reached, the new technique of sentinel node mapping, has cast a shadow on all the answers recently obtained. The complexity of nodal drainage, the relatively low frequency of nodal disease, inadequate staging, and slight, if any, therapeutic benefit are clear obstacles in attempting to demonstrate any benefit of elective nodal dissection for melanoma. Now the wholesale removal of entire nodal basins that may harbor metastatic disease based on inadequate descriptions of drainage patterns, and insensitive pathologic techniques should no longer be performed. Regardless of possible therapeutic benefit, sentinel node biopsies efficiently predict prognosis with low morbidity. Unlike in breast cancer, there is no clearly beneficial adjuvant therapy available for high-risk patients, but as various new melanoma therapies are being developed, risk stratification by nodal status will become increasingly important. Does melanoma spread stepwise through the draining lymph nodes before reaching other more distant sites, or, as in breast cancer, does a Fisherian theory of nodal disease exist in which positive nodes are only a marker for systemic disease Patients with tumor less than 1 mm deep have a 98% cure rate and would not benefit from a relatively morbid operation. One of the most important criticisms was that up to 80% of patients had negative nodes on pathology. Many believe that lymph node metastases are a manifestation rather than a predecessor of distant spread. Ten percent of metastases were positive in the contralateral node, and 6% were positive in nodal basins not classically predicted. As is true for squamous cell cancers of the head and neck, evidence arising from randomized prospective trials is not available to confirm the value of prophylactic nodal dissection for melanoma arising in the head and neck. This demonstrated the lack of reliability of retrospective trials and the length of time needed for adequate data accrual. Multivariate analysis showed that routine use of immediate node dissection had no effect on survival. The concept of sentinel node biopsy is based on the presumption of an orderly progression of disease through the lymphatic system.
The same authors conducted a randomized trial of identical design with 57 patients undergoing autologous transplantation. No differences were observed in transfusion requirement or hematopoietic recovery. It is standard practice to treat all neutropenic, febrile patients with broad-spectrum antibiotics, even though many patients do not have documented infections. This adversely affects quality of life, increases hospital costs, and often results in reduction of chemotherapy doses for subsequent cycles. Further, length of hospital stay, incidence of confirmed infections, and days of antibiotic use were reduced by approximately 50%. In none of these randomized studies was there a clear difference in mortality, tumor response rate, or survival. Such patients would include those with reduced marrow function (due to prior pelvic radiation therapy, prior extensive chemotherapy, or marrow involvement with tumor); those with preexisting neutropenia for any reason; those with any other preexisting immune dysfunction; those with active infection; and those with a documented previous episode of chemotherapy-induced febrile neutropenia or infection. Summary of American Society of Clinical Oncology Guidelines for Administration of Granulocyte Colony-Stimulating Factor and Granulocyte-Macrophage Colony-Stimulating Factor One of the inevitable problems faced by authors of guidelines is in defining what constitutes a benefit. However, the larger question of whether the entire treatment program of aggressive chemotherapy with growth factor (or stem cell) support has led to a clinically significant benefit for the patient as compared to standard treatment has often not been addressed. The reported phase I studies suggest that escalation of chemotherapy drug dose to levels higher than "standard" has often been possible. However, this approach overall has had limited success, in part due to the fact that thrombocytopenia and nonhematologic side effects often emerge quickly as dose-limiting toxicities. Twenty-two of 48 patients were withdrawn from the study, including 12 patients with sepsis (4 fatal) or grade 4 thrombocytopenia. For standard regimens in which the expected incidence of treatment delay or dose reduction is high. The value of dose maintenance will need to be established, however, by prospective, randomized trials in each tumor type. In some, but not all, of these studies, hospital stay, antibiotic use, infections, or platelet transfusions were also reduced. There has been no evidence of reduced mortality or increase in tumor response rates. However, interpatient variability is substantial, and mobilization is generally reduced in patients with extensive prior exposure to chemotherapy or radiation, particularly to the pelvis. The mobilized cells may be more immature than the progenitor cells that are resident in the blood of untreated individuals. This approach seems reasonable at present in autologous transplantation, but additional studies are needed in allogeneic transplants of blood stem cells. Tumor cell contamination of progenitor cells collected from the blood could limit the success of these products for autologous transplantation, as is the case for autologous marrow transplantation. However, currently only limited expansion of hematopoietic stem cells has been achieved, and there is the potential that there will not be enough true hematopoietic stem cells to effect long-term permanent reconstitution if these expanded populations are used in transplantation settings. It is possible that there are yet unknown cytokines that will induce stem cell proliferation while inhibiting differentiation, and such cytokines might be ideal for this process. Alternatively, expanded progenitor cells may have some uses, even if the stem cell content is decreased. For example, progenitor cells may be useful to accelerate hematopoietic recovery after myelosuppressive, but not myeloablative, chemotherapy regimens. Thus, administration of either factor carries the risk of promoting leukemic cell proliferation. There was a 1-week reduction in the duration of severe neutropenia but no decrease in antibiotic use or hospital stay. There was no significant difference reported in rate of complete remission or overall survival. However, there was no reduction in the incidence of severe infections or any difference in complete remission rate or overall survival. The study drug was started on day 11 if a day-10 marrow was hypoplastic, and patients who entered complete remission received the study drug after consolidation therapy as well. There was no difference in remission rate, incidence of severe infections, or early deaths. Of 82 evaluable patients, 66% had an increase in neutrophil count of twofold or more during the study, but sustained neutrophil responses, red cell responses, and platelet responses were rare. Both factors appear to reduce myelosuppression, but there is no clear effect on response rates or rates of infection.
Primarily, they are proliferative and malignant tumors that tend to spread throughout the neuraxis like medulloblastoma. Surgical principles are the same as those for cerebral astrocytoma described earlier. Although radiation therapy appears to improve survival time, the outcome is generally poor, and most patients develop local or regional recurrences. Because of their propensity to spread throughout the subarachnoid space, primitive neuroectodermal tumors are treated with craniospinal axis irradiation. The primary tumor is given 54 to 56 Gy and the remainder of the axis receives 36 Gy. Whereas in some series 1-year survival rates are as low as 10%, 293 others report 5-year survival rates of 20% to 25%. None of the patients with tumors containing more than 90% undifferentiated elements were alive at 3 years, whereas 60% of those with less primitive tumors survived 3 years. They tend to be less malignant, have a better outcome, and are less likely to disseminate throughout the craniospinal axis. Berger and colleagues found that 7 of the 11 patients treated with local irradiation to an average of 52 Gy were alive with no evidence of tumor progression. The only patient with a solid lesion who did not have a recurrence received adjuvant chemotherapy. Although subarachnoid dissemination is found in autopsied cases, 301 this pattern of spread does not represent a significant clinical problem. Thus, localized cerebral neuroblastomas are treated with involved field irradiation to 54 Gy. Reports of isolated cases and small series indicate that drugs active against medulloblastoma have activity in primitive neuroectodermal tumors (see Medulloblastoma Chemotherapy section, later in this chapter). Although the cell of origin of these tumors is controversial, it is probable that medulloblastoma takes its origin from germinative neuroepithelial cells in the roof of the fourth ventricle. The typical location for childhood medulloblastoma is in the cerebellum, mostly in the midline and posterior vermis. In adolescents and adults, there is an increasing tendency for tumors to be laterally placed in the cerebellar hemispheres. Regardless of where in the cerebellum they occur, the tendency for metastatic spread (within craniospinal intradural axis) of medulloblastoma is relatively high. At presentation, as many as 30% of patients have positive cytology or myelographic evidence of spinal metastasis. There is arcuate stretching and displacement of the medulla and secondary hydrocephalus. The well-circumscribed nature and location of the tumor is fairly characteristic for medulloblastoma. Based on bromodeoxyuridine 30-minute labeling indices, medulloblastoma would be considered a highly proliferative tumor because its labeling index is approximately 14%, as opposed to gliomas, which range between less than 1% to 10%. However, in most patients, if the surgeon can remove more than 75% of tumor, the resection is usually a gross total resection. Most radiation therapists do not treat with full doses of craniospinal irradiation at 4 years of age. The disease-free survival of poor-risk patients with craniospinal irradiation with or without chemotherapy is approximately 25% to 30%. In as many as 60% of patients, aggressive resection of the tumor relieves hydrocephalus. The incision and bony exposure are usually in the midline, but a paramedian incision and unilateral bony removal are done when the tumor is limited to one hemisphere, particularly in adults. The more commonly used midline craniectomy extends down through the foramen magnum, and a laminectomy of C-1 (and rarely, C-2) is performed to decompress herniated cerebellar tonsils or to remove a caudally extending tongue of tumor over the dorsum of the spinal cord. After the dura is opened, the cerebellar tonsils are retracted laterally, and it is in the foramen of Magendie that the purplish-gray tumor usually is first seen. The floor of the fourth ventricle is separated from the tumor by a cottonoid pledget.
Taxol: a unique antineoplastic agent with significant activity in advanced ovarian epithelial neoplasms. Paclitaxel administration to gynecologic cancer patients with major cardiac risk factors. Combining new agents with anthracyclines in metastatic breast cancer: an overview of recent findings. Vincristine treatment of acute lymphoblastic leukemia induces transient autonomic cardioneuropathy. Acute vascular toxicity after combination chemotherapy with cisplatin, vinblastine, and bleomycin for testicular cancer. Infarct-typical changes in the electrocardiogram following chemotherapy with vinblastine. A prospective study on the dose dependency of cardiotoxicity induced by mitomycin C. Six case reports and review of the literature on renal, pulmonary and cardiac side effects of the drug. Cardiotoxicity of high-dose continuous infusion fluorouracil: a prospective clinical study. Adverse cardiac effects during induction chemotherapy treatment with cis-platin and 5-fluorouracil. Hypotension as a manifestation of cardiotoxicity in three patients receiving cisplatin and 5-fluorouracil. Correlation of 5-fluorouracil distribution in rodents with toxicity and chemotherapy in man. Paroxymal supraventricular tachycardia during treatment with cisplatin and etoposide combination. Acute vascular ischemic events after cisplatin-based combination chemotherapy for germ-cell tumors of the testis. Reversible arrhythmias observed in patients treated with recombinant alpha 2 interferon. Cardiotoxicity as a dose-limiting factor in a schedule of high dose bolus therapy with interleukin-2 and alpha-interferon. Effect of interferon, interleukin-2 and tumor necrosis factor on myocardial cell viability and doxorubicin cardiotoxicity in vitro. Recombinant interleukin-2 and recombinant interferon a immunotherapy cardiovascular toxicity. A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cell and interleukin-2 or high dose interleukin alone. Metastatic renal cancer treated with interleukin-2 and lymphokine-activated killer cells. Cardiopulmonary toxicity of treatment with high dose interleukin-2 in 199 consecutive patients with metastatic melanoma or renal cell carcinoma. Cardiotoxicity in patients receiving trastuzumab (Herceptin): primary toxicity, synergistic or sequential stress, or surveillance artifact In vivo and in vitro cardiotoxicity of a gold-containing antineoplastic drug candidate in the rabbit. The roleof histamine in doxorubicin and teniposide-induced cardiotoxicity in dog and mouse. Possible cardiac side effects of granisetron, an antiemetic agent, in patients with bone and soft-tissue sarcomas receiving cytotoxic chemotherapy. Radiation-induced heart disease: review of experimental data on dose response and pathogenesis [Review]. Radiation heart disease: analysis of 16 young (aged 15 to 33 years) necropsy patients who received over 3,500 rads to the heart. Pathology of radiation-induced heart disease: a surgical and autopsy study of 27 cases. Long-term cardiovascular evaluation of patients treated by thoracic mantle radiation therapy.
Therefore, it is no longer appropriate to offer prophylactic surgery until a patient is referred for genetic counseling and, if possible, testing (Table 56. Management of hereditary melanoma patients involves frequent full-body examination by a dermatologist familiar with pigmented lesions. Semiannual appointments typically include photography of the entire body, to allow for objective determination of differences in size or appearance of moles, and subsequent excision of any suspicious lesions. Surveillance and risk reduction for patients who are known mutation carriers for such conditions may decrease the associated morbidity and mortality of these syndromes. Some programs provide patients with an annual or biannual newsletter updating them on new information in the field of cancer genetics. A small proportion of patients may return for a follow-up counseling session months, or even years, after their initial consult to discuss the emergence of new family history data and new clinical issues or because they are now ready to move forward with genetic testing. Just the process of scheduling a cancer risk counseling session may be fairly difficult for some individuals with a family history who are not only frightened about their own cancer risk but are reliving painful experiences associated with the cancer of their loved ones. Some counselees are wrestling with the fear that insurance companies, employers, family members, and even future partners will react negatively to their cancer risks. For many, it is a double-edged sword as they balance their fears and apprehensions about dredging up these issues with the possibility of obtaining reassuring news and much-needed information. Some first-degree relatives of women with breast cancer said they felt as though they were living with a sword over their heads or that they were walking time bombs. More than one-third of these nonaffected women reported breast cancer images and associations that intruded on their awareness, and 20% had difficulty in sleeping because of their breast cancer concerns. Importantly, these authors found that genetic counseling was significantly less effective among women with higher baseline levels of breast cancer preoccupation. Therefore, they concluded that efforts to provide individuals with cancer genetic counseling are not likely to be effective unless their cancer anxieties and feelings are also addressed. It is theorized that perhaps these individuals believe that they will definitely develop breast cancer and are helpless in decreasing their risks, or perhaps they are completely immobilized by their fear or denial. Whatever the reason for these behaviors, it is obvious that psychological and educational interventions should be a component of cancer genetic counseling. The counseling session is an opportunity for individuals to express why they believe that they have developed cancer or why their family members have cancer. Some explanations may revolve around family folklore, and it is important to listen to and address these explanations rather than to dismiss them. Predisposition testing may also be appropriate if it will be useful to the minor child in making reproductive decisions now or in the near future. Their willingness to have their children undergo testing appeared to be dependent on the accuracy of the test and the availability of preventive or curative options. Parents may have a constitutionally protected right to demand that unwilling physicians order this test, but there is little risk for liability for damages unless the child experiences physical harm as a direct result of this refusal. Whenever childhood testing is not medically indicated, it is preferable that testing decisions be postponed until the children are adults and can decide for themselves whether to be tested. However, the argument has been made that if a child younger than 18 years is able to appreciate not only the genetic facts but also the emotional and social consequences, he or she should be allowed to have genetic testing. Many programs are opting to keep shadow files separate from the general hospital charts. Patient-identifying data are generally not entered into computer databases that are accessible by modem or a network of users. Special precautions to protect confidentiality should be taken when leaving voice mail messages, at home and at work, regarding patient appointments. Conversations with patients or other colleagues via E-mail that include patient names are discouraged, as the Internet is not secure. Additionally, genetic counseling summary letters are sent directly to patients and are copied to the referring physicians only with the explicit permission of the patient. These measures are taken because confidentiality and genetic discrimination are a grave concern for many of the patients seen in the cancer genetic counseling clinic. Under confidentiality codes, the patient should grant permission before at-risk family members can be contacted.
Alteration in a new gene encoding a putative membrane-organizing protein causes neurofibromatosis type 2. Molecular cloning and characterization of alternatively spliced transcripts of the mouse neurofibromatosis 2 gene. Allelic loss of chromosome 1p is a predictor of unfavorable outcome in patients with neuroblastoma. Human neuroblasotma cytogenetics: search for significance of homogeneously staining regions in double minute chromosomes. A novel chromosome abnormality on human neuroblastoma and anti-folate resistant Chinese hamster cell lines in culture. Decreased expression of N-myc precedes retinoic acid induced phenotypic differentiation of human neuroblastoma. Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Expression of the gene for multidrug-resistance-associated protein and outcome in patients with neuroblastoma. Rhabdomyosarcoma in children: a histological and immunohistochemical study of 59 cases. Myogenic regulatory protein (MyoD1) expression in childhood solid tumors: diagnostic utility in rhabdomyosarcoma. Chromosomal localization of the human rhabdomyosarcoma locus by mitotic recombination mapping. A model for embryonal rhabdomyosarcoma tumorigenesis that involves genome imprinting. Common and variant gene fusions predict distinct clinical phenotypes in rhabdomyosarcoma. Detection of point mutations in N-ras and K-ras genes of human embryonal rhabdomyosarcomas using oligonucleotide probes and the polymerase chain reaction. Rhabdomyosarcoma in children: epidemiologic study and identification of a familial cancer syndrome. Germline transmission of a mutated p53 gene in a cancer-prone family with Li-Fraumeni syndrome Nature 1990;348:747. Two Li-Fraumeni syndrome families with novel germline p53 mutations: loss of the wild-type allele in only 50% of tumors. Germline mutations of the p53 tumor suppressor gene in patients with high risk for cancer inactivate the protein. Germline p53 mutations are frequently detected in young children with rhabdomyosarcoma. Germline mutations of the p53 tumor suppressor gene in children with osteosarcoma. The role of the human homologue of Drosophila patched in sporadic basal cell carcinomas. The gene for the naevoid basal cell carcinoma syndrome acts as a tumour-suppressor gene in medulloblastoma. Collaborative, multimodality treatment efforts undertaken in the context of pediatric cooperative group clinical trials have produced a remarkable improvement in survival since the 1970s. In addition to improvements in survival and functional outcome, the cooperative group studies have also facilitated a rapid growth in our understanding of cancer genetics and tumor biology. Prospective studies are currently underway to validate new risk group stratification schemes that integrate classical tumor staging information with prognostically significant features of tumor biology detectable with molecular diagnostics. We review the epidemiology, pathology, clinical presentation, evaluation, treatment, and prognosis of the common malignant solid tumors of children and adolescents. In 1998, the most recent year for which statistics are available, accidents, congenital anomalies, and homicide were responsible for more deaths in the age group 1 to 4 years, whereas only accidents were a more frequent cause of death in the age group 5 to 14 years. Children Insights into the etiology of malignant solid tumors of childhood have been suggested by well-designed case-control studies (Table 44. Risk of Solid Tumors Following Parental Preconception Exposures Some childhood solid tumors occur in association with well-recognized single gene defects. A tumor arises only if a second event occurs, resulting in the loss of function of the remaining normal allele. Effective combination chemotherapy regimens have been identified and evaluated through cooperative group multiinstitutional trials.
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