Hybrid fitness, adaptation and evolutionary diversification: lessons learned from Louisiana Irises.

Estimates of hybrid fitness have been used as either a platform for testing the potential role of natural hybridization in the evolution of species and species complexes or, alternatively, as a rationale for dismissing hybridization events as being of any evolutionary significance. From the time of Darwin's publication of The Origin, through the neo-Darwinian synthesis, to the present day, the observation of variability in hybrid fitness has remained a challenge for some models of speciation. Yet, Darwin and others have reported the elevated fitness of hybrid genotypes under certain environmental conditions. In modern scientific terminology, this observation reflects the fact that hybrid genotypes can demonstrate genotype × environment interactions. In the current review, we illustrate the development of one plant species complex, namely the Louisiana Irises, into a 'model system' for investigating hybrid fitness and the role of genetic exchange in adaptive evolution and diversification. In particular, we will argue that a multitude of approaches, involving both experimental and natural environments, and incorporating both manipulative analyses and surveys of natural populations, are necessary to adequately test for the evolutionary significance of introgressive hybridization. An appreciation of the variability of hybrid fitness leads to the conclusion that certain genetic signatures reflect adaptive evolution. Furthermore, tests of the frequency of allopatric versus sympatric/parapatric divergence (that is, divergence with ongoing gene flow) support hybrid genotypes as a mechanism of evolutionary diversification in numerous species complexes.

Primary thyroid carcinoma in children: a retrospective study of 20 patients.

A total of 20 children (median age 11 years) were treated for primary thyroid carcinoma from 1976 to 1990. Papillary adenocarcinoma was diagnosed in 19 and follicular in one case. Nineteen of 20 patients were considered amenable to surgery, which consisted of total thyroidectomy in 14 and partial thyroidectomy in 5. Only one patient with extensive perithyroid soft tissue infiltration was treated with external beam radiotherapy. Monolateral or bilateral cervical nodal dissection was performed in eight and six children, respectively; in nine cases without clinical evidence of metastatic nodes. Pathological examination showed that tumor extent was greater than that clinically assessed: Multiple tumor foci within the thyroid were assessed in 8/19, unilateral positive nodes in 8, and bilateral in 6, and soft tissue infiltration in 7. Subsequently 10 patients received thyroid-stimulating hormone (TSH) suppressive hormonotherapy. Relapses occurred in 7/20 at 2-48 months (median 18) from primary treatment: Four in cervical nodes, two in cervical nodes and lungs, and one in lungs. These seven patients were salvaged with node dissection and radioiodine therapy for lung metastases. All the 20 children are alive and disease-free after a median follow-up of longer than 10 years. The incidence of relapse was greater in the group of patients not given TSH-suppressive hormonotherapy. Total thyroidectomy produced permanent hypoparathyroidism in 5/14 (36%). Thyroid carcinoma in children of this series frequently presented with multiple tumor foci within the thyroid and cervical node metastases. Prognosis was favourable even after relapse and was not related to the extent of surgical treatment. Limited surgery and suppressive hormonotherapy may be adequate therapy for thyroid carcinoma in children.

Long-term outcome of patients with monostotic Ewing's sarcoma treated with combined modality.

One hundred and twenty-one consecutive patients with monostotic Ewing's sarcoma (ES) were treated according to three consecutive combined modality programs from 1974 to 1986. Their 3-year progression free survival (PFS) rate from diagnosis of 59% was identical to the event free survival (EFS) rate, since all the 50 events occurring within 3 years from diagnosis were tumor recurrences. Primary tumor was treated with radiotherapy in 75 cases, surgical resection plus radiotherapy in 38, and radical surgery in 8. Chemotherapy was given to all patients and each program included adriamycin, vincristine, and cyclophosphamide +/- dactinomycin. Median follow-up was 12 years, ranging from 6 to 19 years. The PFS rate decreased to 49% at 6 years and plateaued at 46% after the 7th year from diagnosis, even though some relapses were observed as late as 14 years from diagnosis. Second malignancies developed in 7 patients free from progressive ES and were represented by osteogenic sarcoma in previously irradiated bone in 4 cases and by breast carcinoma in 3. No other event but tumor relapse or second malignancy occurred in this series. EFS rate was 47% at 6 years and 39% at 12 years, further decreasing in the following years because of a number of late events. A continuous PFS longer than 7 years may be consistent with cure in the majority of patients with monostotic ES. However, these patients should be followed indefinitely because of risk of second malignancies.

Curability of advanced Burkitt's lymphoma in children by intensive short-term chemotherapy.

The treatment programme (regimen I) we designed in 1982 for advanced Burkitt's lymphoma was modified in 1986 as regimen IIA and IIB for patients presenting without or with bone marrow (BM) and/or nervous system involvement, respectively. Following a 5-week course of cytoreductive chemotherapy, including vincristine (VCR), cyclophosphamide (CPM), doxorubicin (DXR), high-dose methotrexate (HDMTX) and intrathecal methotrexate and cytarabine (ARAC), high-dose ARAC and cisplatin were given as a 4-day continuous infusion. Regimen I continued with an additional 3-week course including VCR, CPM, DXR and HDMTX, which was omitted in regimen IIA. In regimen IIB the initial cytoreductive chemotherapy was complemented by adding etoposide and increasing HDMTX doses, and by modifying the high-dose ARAC administration modality and was followed, once the bone marrow had recovered, by ifosfamide that concluded the programme. A total of 44 children (22 in regimen I and 22 in regimens IIA and IIB) were treated, with an overall response rate of 98%. 4 patients died as a result of treatment related complications. Survival, progression-free and event-free survival rates were 73, 70 and 63%, respectively, for regimen I, and 82, 90 and 82%, respectively, for regimen IIA and IIB. A short chemotherapeutic regimen, using alternating phase-specific and non-specific agents, is able to cure the majority of patients with advanced Burkitt's lymphoma.

Combined treatment modality for medulloblastoma in childhood: effects on neuropsychological functioning.

8 long-surviving children, treated for medulloblastoma with combination radiotherapy and chemotherapy after surgery were examined in order to assess general intelligence, immediate attention and prolonged attention. Their siblings or first cousins were selected as controls. The children with medulloblastoma performed significantly worse than their peers, both in intelligence tests and attention tests. A trend towards a positive correlation between age at the start of treatment and IQs was confirmed in our study, while there was no evidence of a correlation between IQs and time elapsed from therapy. The role of chemotherapy, radiotherapy and their combination effect in producing neuropsychological sequelae is discussed.

Nephroblastoma with neuroendocrine differentiation.

A nephroblastoma (Wilms' tumor) with morphological, histochemical, immunohistochemical and ultrastructural evidence of neuroendocrine differentiation is described. Whereas areas of neural differentiation and occasional argyrophilic cells in cases of Wilms' tumor have been previously reported, the unique characteristic in this case was the extent of the neuroendocrine differentiation, as shown by a strong Grimelius stain of over 90% of the blastematous cells. Immunoperoxidase studies employing antibodies to neuron-specific enolase and ultrastructural data were also in favor of the neuroendocrine differentiation and suggested the existence, in addition to the already reported variant of Wilms' tumor with neural differentiation, of a neuroendocrine variant which may be part of the histologic spectrum of this neoplasm.

Combined radiotherapy and chemotherapy in stage T3 and T4 nasopharyngeal carcinoma in children.

Twelve children younger than 16 years affected by undifferentiated nasopharyngeal carcinoma (NPC) with advanced primary tumor (T3, T4) were treated with chemotherapy consisting of Adriamycin (ADM [doxorubicin; Adria Laboratories, Columbus, OH]), vincristine (VCR), and cyclophosphamide (CYC), and radiotherapy. Preradiation chemotherapy produced partial responses in eight of ten evaluable patients. Eleven of 12 patients achieved a complete response following radiotherapy. The actuarial 3-year continuous relapse-free survival (CRFS) was 75%. This represents a significant improvement when compared with the 8% rate obtained in a previous series of patients treated with radiotherapy either with or without adjuvant CYC.