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Role of adjuvant chemotherapy in the treatment of surgically resected pediatric nonrhabdomyosarcomatous soft tissue sarcomas: a Pediatric Oncology Group study medicine over the counter amoxicillin 500 mg purchase free shipping. Metastatic nonrhabdomyosarcomatous soft-tissue sarcomas in children and adolescents: the St. Key support services should include pathology, diagnostic imaging, rehabilitation (physical/occupational/speech therapy), nutrition, and psychosocial services (social work, child life, psychology, chaplain). Although the general approach to children with these tumors is often similar to that for adults, important differences exist. Primary tumor resections might be complicated by the small amount of surrounding normal anatomic structures and may result in deformity or disability that is lifelong. Limb-sparing procedures in younger children are more difficult to perform, but newer techniques and expandable prostheses may allow for a greater number of these procedures. Chemotherapy carries risks, including infertility, cardiomyopathy, renal dysfunction, and secondary neoplasia, that may be of greater concern in children. Late effects are of particular concern in young children, whose potential survival after successful therapy is much longer. The goal of therapy is to achieve longterm disease control with minimum morbidity in both the short and long term. The first therapeutic consideration is to determine how to best achieve local control. When feasible, a complete surgical resection should be performed with the goal of excising the primary tumor with margins sufficient to prevent local recurrence. If, at diagnosis, the tumor cannot be widely resected with acceptable morbidity, other strategies should be considered. Adjuvant radiotherapy produces adequate local tumor control after a marginal tumor resection. These treatment modalities are discussed in more detail in the sections that follow. Surgical Evaluation and Treatment Approaches the surgeon plays a key role in the initial diagnosis and staging. The surgeon must first ensure that the local diagnostic imaging staging of the tumor is complete prior to biopsy. When possible, the surgeon who will perform the definitive surgical approach should evaluate the patient prior to the biopsy to assist in determining the appropriate approach. The biopsy incision or track will need to be excised at the time of definitive surgery. It is essential that sufficient diagnostic material be obtained for these biologic studies. Depending on local expertise, the surgeon, radiologist, or pathologist may perform the biopsy. The presence of an experienced cytopathologist nearby when the biopsy is being performed is also important.
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Final height after treatment for childhood acute lymphoblastic leukemia: comparison of no cranial irradiation with 1800 and 2400 centigrays of cranial irradiation medications for bipolar disorder buy amoxicillin 250 mg amex. Disturbance in bone turnover in children with a malignancy at completion of chemotherapy. Liver function studies in children with acute lymphocytic leukemia after cessation of therapy. Anthracycline dose in childhood acute lymphoblastic leukemia: issues of early survival versus late cardiotoxicity. Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia in childhood. Are children with lesser-risk B-lineage acute lymphoblastic leukemia curable with antimetabolite therapy Normal or early development of puberty despite gonadal damage in children treated for acute lymphoblastic leukemia. Effect of childhood acute lymphoblastic leukemia therapy on spermatogonia populations and future fertility. Evaluation of gonadal function following long-term treatment for acute lymphoblastic leukemia in girls. Second malignancies in patients treated for childhood acute lymphoblastic leukemia. Parotid carcinoma as a second malignancy after treatment of childhood acute lymphoblastic leukemia. Second malignant tumors after elective end of therapy for a first cancer in childhood: a multicenter study in Italy. Ponte di Legno Working Group: statement on the right of children with leukemia to have full access to essential treatment and report on the Sixth International Childhood Acute Lymphoblastic Leukemia Workshop. Chapter 20 Acute Myeloid Leukemia, Myeloproliferative and Myelodysplastic Disorders Todd M. Smith the term myeloid includes all of the cells belonging to the granulocytic (neutrophilic, eosinophilic, basophilic), monocytic/macrophage, erythroid, megakaryocytic, and mast cell lineages. Myeloid malignancies result from abnormalities in genes that control cellular proliferation, survival, and differentiation. Myeloproliferative disorders are characterized by the excessive proliferation of relatively normally differentiated hematopoietic cells. These differences are reflected in the morphology, cytogenetics, and clinical presentation of the two distinct age groups. For example, adults often present with a more indolent disease course characterized by an isolated anemia and associated with del(5q) chromosome. Not surprisingly, myeloid neoplasms share common etiologies, which will be discussed here Table 20. Primary and Secondary Myeloid Neoplasms A neoplasm can arise in a previously healthy child and is conformingly named " de novo" or "primary. It is to be recognized, however, that among the children with so-called "primary" neoplasms, some may have an underlying, yet unknown, predisposing genetic defect.
The surgical management of children with incompletely resected hepatic cancer is facilitated by intensive chemotherapy medications causing hyponatremia 250 mg amoxicillin with amex. Cisplatin, doxorubicin, and delayed surgery for childhood hepatoblastoma: a successful approach-results of the first prospective study of the International Society of Pediatric Oncology. Surgical view of the treatment of patients with hepatoblastoma: results from the first prospective trial of the International Society of Pediatric Oncology Liver Tumor Study Group. Port site recurrences after laparoscopic and thoracoscopic procedures in malignancy. Risk-based management: current concepts of treating malignant solid tumors of childhood. Prognostic factors predictive of survival and local recurrence for extremity soft tissue sarcoma. The hazards of biopsy in patients with malignant primary bone and softtissue tumors. Advances in bone tumour treatment in 30 years with respect to survival and limb salvage: a single institution experience. Influence of local recurrence on survival in patients with extremity osteosarcoma treated by neoadjuvant chemotherapy: the experience of a single institution with 44 patients. Risk factors for local recurrences after limb-salvage surgery for high-grade osteosarcoma of the extremities. Quality of life in survivors with a Van Ness-Borggreve rotationplasty after bone tumour resection. Embryonal carcinoma of the ovary: a clinicopathologic entity distinct from endodermal sinus tumor resembling embryonal carcinoma of the adult testis. Embryonal adenocarcinomas (a type of malignant teratoma) of the sacrococcygeal region: clinical and pathologic aspects of 21 cases. Cis-diamminedichloroplatinum, vinblastine, and bleomycin combination chemotherapy in disseminated testicular cancer. Cisplastin-based combination chemotherapy for disseminated germ cell tumors: long-term follow-up. Outcome and staging evaluation in malignant germ cell tumors of the ovary in children and adolescents: an Intergroup study. History of the surgical management of pulmonary metastases and development of the International Registry. Kun Radiation oncology is a clinical discipline focused on utilization of radiation therapy as a physical means of producing a biologic effect. The production and targeted delivery of ionizing radiations to a patient relies on the principles and accuracy of radiation physics. The goal of radiation physics is to deliver the prescribed radiation dose to a carefully identified target volume, relatively sparing adjacent normal tissues. The biologic basis of radiation therapy includes cell- or tissue-specific inherent radiosensitivity but relies primarily on optimally exploiting differences in tumor and normal tissue responses to ionizing radiations based on the time:dose relationship and modifiers of radiation response. Empiric investigations during the past century established the basis for fractionated radiation delivery protracted over several weeks to optimize differences between normal tissues and tumor in both repair of sublethal radiation injury and changes in the tumor microenvironment.
The agent was relatively well tolerated in adults with the dose-limiting toxicities being liver enzyme elevations and fatigue symptoms 5 days before missed period amoxicillin 500 mg cheap. Phase 2 studies of imatinib for children with solid tumors found little or no activity against all histologies evaluated,342 despite confirmed expression of one or more target receptor tyrosine kinases in many of the cases. These mutations are observed in approximately 60% of melanomas, as well as 40% of thyroid cancers, and 20% of colon cancer and ovarian cancer. Temsirolimus at a weekly dose of 25 mg administered intravenously is licensed for treatment of previously untreated, metastatic renal cell carcinoma based on phase 3 trial results showing improved survival for patients receiving temsirolimus compared with that for patients receiving interferon alfa. Objective responses to rapamycin have been observed in tuberous sclerosis patients with subependymal giant cell astrocytomas, providing evidence for sufficient rapamycin brain penetration for clinical effect. However, there is evidence from studies of immature mice for a continued role for the Hedgehog pathway postnatally, as short-term treatment with pathway inhibitors leads to permanent bone damage. Pediatric evaluations of this class of agents will require careful monitoring for skeletal growth complications, given the bone effects observed for Hedgehog pathway inhibitors in immature mice. The concept of combining an agent that depletes the cancer stem cell population with conventional therapy that induces tumor debulking is an attractive, though unproven, application of Hedgehog pathway inhibitors. Targeting Notch Pathway Signaling Notch pathway signaling is implicated in a wide range of developmental and cellular processes, including carcinogenesis. Each of these classes of inhibitors has a strong preclinical package, with potent in vitro activity and convincing in vivo activity against a range of xenografts. Given the specificity of these agents for actively dividing cells, they share a similar clinical toxicity profile in which neutropenia and/or thrombocytopenia are common dose-limiting toxicities. Histone acetylation alters chromatin structure and induces a local chromatin environment conducive with gene transcription, whereas histone deacetylation is commonly associated with repression of transcription. Additional substrates include nuclear proteins such as p53, myo-D, and E2F1 and cytoplasmic proteins such as a-tubulin and Hsp90. Polyubiquitinated proteins are recognized by the proteasome and degraded into small polypeptides. A subsequent phase 3 trial demonstrated that bortezomib was significantly more effective than dexamethasone for patients with relapsed multiple myeloma who had received one to three previous therapies. Targeting Angiogenesis From 1971 when Folkman proposed targeting angiogenesis as a potential effective strategy for cancer treatment,503 three decades were required to prove that antiangiogenic therapy could improve survival for patients with cancer. Glioblastoma is a tumor characterized by vascular proliferation and high expression of angiogenic factors, and bevacizumab induces objective responses, either as a single agent or in combination with irinotecan, in adults with glioblastoma. The first study addressing this question was for colorectal cancer, and randomized patients to standard chemotherapy for 6 months with or without 12 months of bevacizumab. The failure of bevacizumab in the adjuvant setting to aid in controlling micrometastatic disease, if confirmed in other studies, has major implications for the use of this class of agents in the pediatric oncology setting, given the primary focus on curative therapy for children with cancer. In vivo testing primarily showed tumor growth delay, with very few examples of tumor regression observed. When treatment was stopped, tumors quickly resumed growth, consistent with results from adult cancer models indicating that continuous treatment is necessary for tumor growth inhibition.
World Health Organization Classification of Tumours: Pathology and Genetics: Tumours of Soft Tissue and Bone medicine hat weather cheap 500 mg amoxicillin otc. Health organization classification of tumours: pathology and genetics: tumours of soft tissue and bone. World health organization classification of tumours: pathology and genetics: tumours of soft tissue and bone. High-grade osteosarcoma of the extremity: differences between localized and metastatic tumors at presentation. Neoadjuvant chemotherapy for osteosarcoma of the extremities with synchronous lung metastases: treatment with cisplatin, adriamycin and high dose of methotrexate and ifosfamide. Treatment of metastatic osteosarcoma at diagnosis: a Pediatric Oncology Group Study. Postrelapse survival in osteosarcoma of the extremities: prognostic factors for long-term survival. Primary metastatic osteosarcoma: presentation and outcome of patients treated on neoadjuvant Cooperative Osteosarcoma Study Group protocols. Improved prognosis of children with osteosarcoma metastatic to the lung(s) at the time of diagnosis [published erratum appears in Cancer 1993;71(9):2879]. Metastases detected at the time of diagnosis of primary pediatric extremity osteosarcoma at diagnosis: imaging features. Skip metastases in osteosarcoma: experience of the cooperative osteosarcoma study group. Prognostic significance of serum alkaline phosphatase in osteosarcoma of the extremity treated with neoadjuvant chemotherapy: recent experience at Rizzoli Institute. Prognostic significance of serum alkaline phosphatase measurements in patients with osteosarcoma treated with adjuvant or neoadjuvant chemotherapy. Predictive factors of disease-free survival for non-metastatic osteosarcoma of the extremity: an analysis of 300 patients treated at the Rizzoli Institute. Radiological appearances of appendicular osteosarcoma: a comprehensive pictorial review. Computed tomography of pulmonary metastases from osteosarcoma: the less poor technique. Midcourse thallium-201 scintigraphy to predict tumor response in bone and soft-tissue tumors. Thallium-201 scintigraphy for the evaluation of tumor response to preoperative chemotherapy in patients with osteosarcoma. Dynamic magnetic resonance imaging of regional contrast access as an additional prognostic factor in pediatric osteosarcoma. Positron emission tomography for staging of pediatric sarcoma patients: results of a prospective multicenter trial.
A result of "no significant difference" is not sufficient medications bipolar cheap amoxicillin 500 mg mastercard, because one can easily assure such a result by designing a study too small to detect a difference even if it is really there. In general, for these types of studies, the preferred design is one in which the minimal difference of interest (usually denoted as d) is specified as the drug effect under the null hypothesis, and the alternative hypothesis is that there is no difference. Thus, the treatments cannot be accepted as equivalent unless one can rule out with high probability that any decrement in effect is no greater than d. Sample sizes for equivalence trials are usually larger than those in difference-seeking trials because physicians are very reluctant to adopt a new treatment that is less effective than current treatments; the decrement in efficacy that must be ruled out in a noninferiority trial is usually smaller that the targeted increase in efficacy in a superiority study. Sample size considerations and other aspects of equivalence/noninferiority study design are discussed in a number of useful refererences. The proper design and interpretation of these trials is complex and is an area of active methodologic research. If we are very sure, then we might want to limit the trial to subjects exhibiting the target, otherwise we might accrue too many subjects who have no chance of showing the effect of the intervention. If there is no reliable assay, then it does not matter whether the biomarker is relevant or not, because we cannot measure the effect of intervention on it. If the target is very common, then even if the therapy is of limited or no value in biomarker negative patients, we should see an overall effect. Otherwise, if the biomarker is rare, then any useful effect in the biomarker positive group, no matter how big, will be diluted by lack of benefit in the overall group. Classic examples of this latter issue from adult oncology (breast cancer) include tamoxifen and the estrogen receptor, which is commonly positive, and trastuzumab and Her-2, which is much less commonly positive. Phase 0 trials are intended to facilitate more rapid development of molecularly targeted agents by allowing first-in-human studies at extremely low, almost certainly subtherapeutic single doses. The purpose is to allow demonstration of drug-target interactions and to gain pharmacokinetic/pharmacodynamic experience that, in theory, would help better design therapeutic trials; there is no therapeutic intent of the phase 0 trial itself. Feasibility Assessment In addition to the statistical considerations discussed earlier, clinical research in children has unique challenges that must be taken into consideration during study design. In addition, for studies evaluating the adverse effects or toxicities of treatment, prolonged follow-up for years following exposure may be required. Studies requiring subject follow-up beyond the age of 18 years require reconsent when the child reaches the age of majority and may be challenging to perform, given issues with patient relocation during adulthood. Even a statistically well-designed study will fail if these kinds of issues make it impossible to complete. Protocol Writing Integral to planning a clinical trial is writing the actual protocol, which can be viewed as an operating manual for the experiment to be conducted.
Syndromes
Impact of body composition on pharmacokinetics of doxorubicin in children: a Glaser Pediatric Research Network study treatment 4 autism generic amoxicillin 250 mg with amex. A phase I study of idarubicin hydrochloride in patients with acute leukemia: the Idarubicin Study Group of Japan. Pharmacokinetics of doxorubicin and its active metabolite in patients with normal renal function and in patients on hemodialysis. Idarubicin metabolism and pharmacokinetics after intravenous and oral administration in cancer patients: a crossover study. Adriamycin chemotherapy: efficacy, safety and pharmacologic basis of an intermittent single high-dosage schedule. Pharmacokinetics and pharmacodynamics of doxorubicin in patients with small cell lung cancer. Acute doxorubicin toxicity: relationship to pretreatment liver function, response and pharmacokinetics in patients with acute non-lymphocytic leukemia. Relationship between toxicity and obesity in women receiving adjuvant chemotherapy for breast cancer: results from cancer and leukemia group B study 8541. A prospective study of topical dimethyl sulfoxide for treating anthracycline extravasation. Time- and dose-dependent changes in ejection fraction determined by radionuclide angiography after anthracycline therapy. Idarubicin cardiotoxicity: a retrospective study in acute myeloid leukemia and myelodysplasia. Cardiac effects of anthracyclines used in the treatment of childhood acute lymphoblastic leukemia: a 10-year experience. Female sex and drug dose as risk factors for late cardiotoxic effects of doxorubicin therapy for childhood cancer. Impact of scheduling on toxicity and clinical efficacy of doxorubicin: what do we know in the mid-nineties Adriamycin given as a weekly schedule without a loading course: clinically effective with reduced incidence of cardiotoxicity. Reduction of doxorubicin cardiotoxicity by prolonged continuous intravenous infusion. Doxorubicin cardiotoxicity in children: comparison of a consecutive divided daily dose administration schedule with single dose (rapid) infusion administration. Doxorubicin cardiotoxicity in children: reduced incidence of cardiac dysfunction associated with continuous-infusion schedules. Doxorubicin administration by continuous infusion is not cardioprotective: the Dana-Farber 91-01 Acute Lymphoblastic Leukemia protocol.
Even more importantly medicine stick cheap 250 mg amoxicillin otc, a byproduct of these early trials demonstrated that tumor response to neoadjuvant chemotherapy became a significant prognostic and therapeutic factor. Furthermore, these studies implemented different chemotherapy regimens for patients without a good response to the neoadjuvant protocol, and this strategy has been shown to be effective by another group. Hepatoblastoma Surgery is the long-standing mainstay in the treatment of hepatoblastoma. However, historical studies document that resection alone seldom achieved cure despite complete removal of all radiographically identifiable disease. In fact, only 25% of children survived who underwent complete resection of their tumors,117,118 and this high failure rate was attributed, as in the osteosarcoma patients, to occult metastatic disease not identified radiographically at the time of the initial resection. Resection of the primary tumor at this point was deemed to balance the maximal effect of neoadjuvant therapy to shrink the tumor prior to the development of chemoresistance. Von Schweinitz and colleagues124 reported that 50% of their patients had evidence of tumor growth after the fourth cycle of neoadjuvant therapy. Ultimately, 5-year survival rates for all patients with hepatoblastoma had increased in just two decades to more than 85% with the addition of neoadjuvant and adjuvant chemotherapy to surgery for hepatoblastoma. The only tumors resected primarily were those deemed to be confined to a single section. Note the resultant decrease in tumor mass by almost 50% (as outlined by white arrows). Minimally Invasive Surgery Over the past 15 years, minimally invasive surgical procedures have become common practice. Improved cameras, new trocar systems, and specifically designed instruments now allow a wide spectrum of operations to be performed without the use of large thoracotomy or laparotomy incisions. In the realm of pediatric surgical oncology, these methods have been most broadly applied to biopsies and the excision of selected masses. Oncologic surgical principles, such as adequate exploration, complete excision of a mass with an appropriate margin, and minimizing the risk of a tumor spill, are still paramount. Although rare and possibly technique-related, trocar site tumor implantation has been reported. Nodules that are located peripherally in the lung, along the parietal pleura, or on the diaphragm are particularly suitable for removal. In larger patients, a double-lumen endotracheal tube allows for selective lung ventilation and, hence, permits more facile surgery. Thoracoscopic surgery to excise small tumors of the lung is frequently accomplished with the aid of an intracorporeal stapling device. Thoracoscopic lobectomy in children is technically feasible, but experience with such resections for primary malignancies remains limited. The mediastinum is also accessible by minimally invasive techniques for thoracoscopically guided needle biopsies, excisional or incisional biopsies, as well as tumor removal in selected individuals. Staging laparoscopy and biopsies of primary and secondary tumors have frequently been performed. If oncologic principles are not compromised, tumor resection may also be considered.
Cytoplasmic processes comprise the centers of the pseudorosettes (hematoxylin and eosin treatment quincke edema amoxicillin 500 mg buy lowest price, original magnification 3,400). Current treatment schedules favor primary induction chemotherapy, followed by local therapy and adjuvant chemotherapy. More recently, improvements in orthopedic surgery have allowed preservation of function without compromising survival rates. From retrospective analyses of several groups, the impression has been that local control is improved when surgery is possible. Surgical Treatment of Ewing Sarcoma the surgical management of malignant bone tumors has evolved and surgical approaches are now a function of the tumor type, location, and extent of disease. In general, patients with an isolated, resectable tumor after induction chemotherapy should have their tumor treated with surgery alone. The goal of any operation on a malignant tumor is to perform a complete, en bloc removal of the lesion with adequate margins. However, in selected cases in which limb salvage may compromise the overall outcome and irradiation would lead to unacceptable morbidity, amputation is warranted. Types of Reconstruction Due to the complexity of the musculoskeletal system, different reconstructive operations are performed depending on the site of involvement. The main reconstructive options include autologous bone grafts, structural bone allografts (intercalary or osteoarticular), and metallic endoprosthetics. Allografts and endoprosthetics may also be used as part of a composite reconstruction. Which technique is employed is a function of the location of the tumor, age of the patient, and types of adjuvant therapies that will be employed. Vascularized autografts, such as the fibula, are attractive because, when successful, the graft incorporates and may even hypertrophy and remodel because of the forces exerted across it. The joint itself may be replaced with an allograft, but functional results are less satisfactory. Extent of anatomic involvement warrants intercalary allograft reconstruction to preserve the native knee joint. For osteoarticular allografts, satisfactory functional results can be anticipated in 60% to 70% of cases in which a high-grade sarcoma was removed and chemotherapy was utilized. Durability of endoprostheses varies, but the anticipated 5-year implant survival for proximal femoral reconstruction approaches 90%, whereas the rate for distal femoral reconstruction is about 60% and for the proximal tibia just over P. Prosthetic reconstructions of the proximal humerus tend to be more durable because they are subject to lesser forces. Failure can result from loosening at the prosthesis-host interface or infection, which in up to a third of patients.
The difference was more pronounced for patients with anaplastic astrocytomas (31 vs medicine yoga 500 mg amoxicillin buy. A caveat worth emphasizing is that factors specific to the tumor, such as the pattern of growth and degree of infiltration, may determine which tumors are amenable to extensive resection. Thus, tumors that are amenable to resection may constitute a group biologically more favorable than those that infiltrate extensively into the surrounding brain. However, hemispheric tumors are more amenable to radical resection than midline tumors. The impact of histology-anaplastic astrocytoma versus glioblastoma multiforme-on outcome is debated. Anaplastic astrocytoma may be favorably prognostic for subsets of patients,104,456 although this association has not been uniformly confirmed, possibly reflecting challenges in the reliable classification of these tumors in historical series. As with the latter tumors, malignant gliomas often are amenable to reoperation at the time of disease progression, because most lesions recur at the primary site. Although the majority of children succumb to further disease progression despite additional intervention, attempted re-resection may be warranted in tumors that are amenable to gross total or radical subtotal removal, in view of reports of long-term survival after extensive resection followed by high-dose chemotherapy. Radiation Therapy Radiation therapy is a standard component of postoperative management for children with malignant gliomas. Although rarely curative, the addition of radiation alone had shown improved survival intervals in adults, and pediatric series demonstrating higher rates of 1- to 3-year disease control and survival have been based on a combination of radiation and chemotherapy. Thus, the benefit of adding chemotherapy to radiation for children with high-grade gliomas is dubious at best, based on currently available studies. However, it is important to point out that anaplastic oligodendroglial tumors of childhood may not be molecularly identical to their adult counterparts499 and, thus, may warrant distinct management approaches. However, this approach is not specific to the tumor cells and the resultant myelosuppression limits the dose of the concomitantly administered cytotoxic agent as has now been observed with both nitrosoureas as well as temozolomide. The imaging characteristics for brainstem tumors in each location are described later. Diffuse Intrinsic Pontine Gliomas Typically, these tumors cause the pons to expand by more than 50% and may infiltrate into the medulla or midbrain. Medullary Tumors Cervicomedullary astrocytomas are a unique group of brainstem tumors with a good prognosis when compared with the diffuse pontine group of brainstem gliomas. Midbrain Tumors Tumors of the midbrain include focal and diffuse midbrain tumors as well as tectal tumors.
Jaroll, 56 years: Endocrinologic sequelae seen are frequent in patients with suprasellar germ cell tumors, including diabetes insipidus, delayed sexual development, panhypopituitarism, diabetes insipidus, and isolated growth failure. Heterogeneity of presenting features and their relation to treatment outcome in 120 children with T-cell acute lymphoblastic leukemia.
Brant, 41 years: Conclusion Improved survival for infants with cancer can be achieved with intensive therapy and the awareness of treatmentrelated toxicity. Notice the cohesive groups of neoplastic cells with high nuclear: cytoplasmic ratio.
Riordian, 34 years: Randomized study of 3 years versus 5 years of chemotherapy in childhood acute lymphoblastic leukemia. Adolescents may be relatively asymptomatic, whereas infants and toddlers more often exhibit severe respiratory symptoms, including hemoptysis or upper airway obstruction.
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