Intragenic recombination events and evidence for hybrid speciation in Nicotiana (Solanaceae).

Reticulate evolution may function both at the species level, through homoploid and polyploid hybridization, and below the species level, through inter and intragenic recombination. These processes represent challenges for the reconstruction of evolutionary relationships between species, because they cannot be represented adequately with bifurcating trees. We use data from low-copy nuclear genes to evaluate long-standing hypotheses of homoploid (interspecific) hybrid speciation in Nicotiana (Solanaceae) and reconstruct a complex series of reticulation events that have been important in the evolutionary history of this genus. Hybrid origins for three diploid species (Nicotiana glauca, N. linearis, and N. spegazzinii) are inferred on the basis of gene tree incongruence, evidence for interallelic recombination between likely parental alleles, and support for incompatible splits in Lento plots. Phylogenetic analysis of recombinant gene sequences illustrates that recombinants may be resolved with one of their progenitor lineages with a high posterior probability under Bayesian inference, and thus there is no indication of the conflict between phylogenetic signals that results from reticulation. Our results illustrate the importance of hybridization in shaping evolution in Nicotiana and also show that intragenic recombination may be relatively common. This finding demonstrates that it is important to investigate the possibility of recombination when aiming to detect hybrids from DNA-sequence data and reconstruct patterns of reticulate evolution between species.

External beam boost for cancer of the cervix uteri when intracavitary therapy cannot be performed.

PURPOSE: To assess the outcome of patients treated with radical radiotherapy for cervical cancer who received an external beam boost, in place of intracavitary brachytherapy (ICT), after irradiation to the whole pelvis. METHODS AND MATERIALS: Case notes were reviewed for all patients treated in this way in a single center between 1996 and 2004. Patient and tumor details, the reasons why ICT was not possible, and treatment outcome were documented. RESULTS: Forty-four patients were identified. The mean age was 56.4 years (range, 26-88 years). Clinical International Federation of Gynecology and Obstetrics or radiologic stage for Stages I, II, III, and IV, respectively, was 16%, 48%, 27%, and 7%. A total radiation dose of 54-70 Gy was given (75% received > or =60 Gy). Reasons for ICT not being performed were technical limitations in 73%, comorbidity or isolation limitations in 23%, and patient choice in 4%. The median follow-up was 2.3 years. Recurrent disease was seen in 48%, with a median time to recurrence of 2.3 years. Central recurrence was seen in 16 of the 21 patients with recurrent disease. The 5-year overall survival rate was 49.3%. The 3-year cancer-specific survival rate by stage was 100%, 70%, and 42% for Stages I, II, and III, respectively. Late Grades 1 and 2 bowel, bladder, and vaginal toxicity were seen in 41%. Late Grade 3 toxicity was seen in 2%. CONCLUSION: An external beam boost is a reasonable option after external beam radiotherapy to the pelvis when it is not possible to perform ICT.

Endometrial adenocarcinoma: an analysis of treatment and outcome.

This study aims to review the survival and morbidity in patients treated for endometrial cancer, at a single centre and analyses the effects of co-morbidity on these outcomes. Case notes of all patients referred to the Christie Hospital with endometrial carcinoma from January 1, 1993 to December 31, 1995 (n=499) were reviewed. Twenty patients presented with recurrence and were not included in this analysis. Three hundred and seventy-five patients had previously undergone a total abdominal hysterectomy and bilateral salpingoophorectomy (+/- pelvic lymphadenectomy). Of these, 175 received adjuvant external beam radiotherapy (XRT) only, 49 received XRT and brachytherapy, 30 received brachytherapy alone and 121 patients had no further therapy. One hundred and four patients were referred for primary treatment. Radical radiotherapy was administered to 63 patients who were unfit for surgery, with 10 of these receiving XRT + brachytherapy and 53 receiving brachytherapy alone. Thirteen patients received palliative XRT and 28 supportive care only. The overall 5-year survival for those treated radically was 73.3%. There was no significant survival difference between patients who underwent surgery and adjuvant radiotherapy, in whatever form (p=0.115). Patients who did not undergo surgery did less well as a group, although there was no significant survival difference between those treated with combination therapy or brachytherapy alone (p=0.33). Survival was significantly associated with FIGO stage, tumour grade, age (especially those >75 years) and co-morbidity (ACE-27 score). Late morbidity occurred in 46 patients, with severe toxicity affecting 12 (3.8%). Toxicity was associated with ACE-27 score (p=0.0019), treatment dose and modality, with 50% (n=6) of severe toxicity seen in patients receiving adjuvant XRT + ICT. These data demonstrate that survival in patients with endometrial carcinoma treated radically remains good, with the stage and grade of tumour being significant factors for overall survival. The incidence of severe morbidity related to radiotherapy of any modality was 3.8%. A high co-morbidity (ACE-27) score was significantly associated with poorer survival (p<0.0055) and increased late treatment morbidity (p=0.0019).

Effectiveness of sports massage for recovery of skeletal muscle from strenuous exercise.

OBJECTIVE: Sport massage, a manual therapy for muscle and soft tissue pain and weakness, is a popular and widely used modality for recovery after intense exercise. Our objective is to determine the effectiveness of sport massage for improving recovery after strenuous exercise. DATA SOURCES: We searched MEDLINE, EMBASE, and CINAHL using all current and historical names for sport massage. Reference sections of included articles were scanned to identify additional relevant articles. STUDY SELECTION: Study inclusion criteria required that subjects (1) were humans, (2) performed strenuous exercise, (3) received massage, and (4) were assessed for muscle recovery and performance. Ultimately, 27 studies met inclusion criteria. DATA EXTRACTION: Eligible studies were reviewed, and data were extracted by the senior author (TMB). The main outcomes extracted were type and timing of massage and outcome measures studied. DATA SYNTHESIS: Data from 17 case series revealed inconsistent results. Most studies evaluating post-exercise function suggest that massage is not effective, whereas studies that also evaluated the symptoms of DOMS did show some benefit. Data from 10 randomized controlled trials (RCTs) do, however, provide moderate evidence for the efficacy of massage therapy. The search identified no trend between type and timing of massage and any specific outcome measures investigated. CONCLUSIONS: Case series provide little support for the use of massage to aid muscle recovery or performance after intense exercise. In contrast, RCTs provide moderate data supporting its use to facilitate recovery from repetitive muscular contractions. Further investigation using standardized protocols measuring similar outcome variables is necessary to more conclusively determine the efficacy of sport massage and the optimal strategy for its implementation to enhance recovery following intense exercise.

The prognostic value of pimonidazole and tumour pO2 in human cervix carcinomas after radiation therapy: a prospective international multi-center study.

BACKGROUND AND PURPOSE: Hypoxia adversely affects treatment outcome in human uterine cervical cancer. Here, we present the results of a prospective international multi-centre study evaluating the prognostic value of pre-treatment tumour oxygen partial pressure (pO(2)) and the hypoxia marker pimonidazole (pimo). MATERIALS AND METHODS: One hundred and twenty-seven patients with primary cervix cancer were entered. Pre-treatment tumour pO(2) measurements were obtained, and reported by the median tumour pO(2), the fraction of pO(2) values

Prediction of radiotherapy outcome using dynamic contrast enhanced MRI of carcinoma of the cervix.

PURPOSE: To investigate whether analysis of MRI enhancement data using a pharmacokinetic model improved a previously found correlation between contrast enhancement and tumor oxygenation measured using PO2 histograph. To evaluate the prognostic value of gadolinium enhancement data for radiotherapy outcome, and to study the efficacy of combined enhancement and MRI volume data. METHODS AND MATERIALS: Fifty patients underwent dynamic gadolinium-enhanced MRI as part of their initial staging investigations before treatment. Gadolinium enhancement was analyzed using the Brix pharmacokinetic model to obtain the parameters amplitude and rate of contrast enhancement. Pretreatment tumor oxygen measurements (Eppendorf PO2 histograph) were available for 35 patients. RESULTS: Both standard and pharmacokinetic-derived enhancement data correlated with tumor oxygenation measurements, and poorly enhancing tumors had low tumor oxygen levels. However, only the pharmacokinetic-analyzed data correlated with patient outcome and patients with poorly (amplitude less than median) vs. well-enhancing tumors had significantly worse disease-specific survival (p = 0.024). For the 50 patients studied, no relationship was found between enhancement and volume data. Combining MRI volume and enhancement information highlighted large differences in outcome (p = 0.0054). At the time of analysis, only 55% of patients with large, poorly enhanced tumors were alive compared with 92% of patients with small, well-enhanced tumors. CONCLUSION: These preliminary results suggest that pharmacokinetic modeling of dynamic contrast-enhanced MRI provides data that reflect tumor oxygenation and yields useful prognostic information in patients with locally advanced carcinoma of the cervix. Combining MRI-derived enhancement and volume data delineates large differences in radiotherapy outcome.

Compensation for changes in dose-rate in radical low-dose-rate brachytherapy: a radiobiological analysis of a randomised clinical trial.

BACKGROUND AND PURPOSE: This study reanalysed the results of the Cs-137 low-dose-rate brachytherapy trials for stage I and II cervix carcinoma at the Christie Hospital, Manchester, UK, in order to quantify the clinical outcome as a function of dose, and to extract radiobiological parameter values by modelling the data for local control and morbidity. PATIENTS AND METHODS: Kaplan-Meier survival curves and Cox regression analyses were used to analyse the time to event data. Linear-quadratic (LQ) analysis was also used in a mixture model, incorporating a half-time for repair, a time factor, and a heterogeneity function between patients. Full 5-year follow-up data were available for 339 patients receiving Cs-137 doses between 60 and 75 Gy delivered at 1.4-1.8 Gy/h, and 178 patients receiving a Ra-226 dose of 75 Gy at 0.5 Gy/h, using two insertions 7-10 days apart. RESULTS: With the increased dose-rate, a dose reduction between 20 and 25% was required to achieve a similar morbidity rate. This reduction had a detrimental effect on tumour control, by about 15% points. Unexpectedly, this loss in local control did not lead to a decrease in cancer-specific survival. For both tumour control and complications a high alpha/beta and short half-time for repair best fitted the data, suggesting that consequential late reactions may be responsible for much of the bowel and urinary morbidity after these short treatments. The variability in response between patients was greater (CV 40%) for morbidity than for tumour control (CV 17%), probably reflecting the greater variation in dose at the target tissue. There was no significant dependence on overall treatment time detected over the 7-10-day range of these treatments. CONCLUSIONS: The therapeutic ratio was somewhat less for the higher dose-rate, in agreement with radiobiological expectations, although cancer-specific survival was inexplicably unchanged. The LQ-parameter analysis suggests that high alpha/beta ratios and/or short repair half-times are applicable for both tumour and normal tissue responses in these treatments.

Training logbook for radiotherapy.

AIM: To develop a structured logbook for trainees in the medical specialty of radiotherapy with Europe that records the increasing experience throughout their training period. MATERIAL AND METHODS: A working party appointed by the European Board of Radiotherapy developed a draft version of a European logbook for trainees in radiotherapy. For development, the update European Core Curriculum for Radiotherapists (Radiation Oncologists) was taken into consideration. The logbook is composed of six sections: (1) biodata of the trainee, (2) scientific training documentation, (3) clinical training documentation, (4) record of formal presentations by the trainee, (5) publications, (6) training courses. Decisions were made to suggest that the clinical section of the logbook should: (a) only collect data that was essential for the purposes of appraisal, assessment and regulation, (b) be as user friendly as possible, (c) concentrate on quality of the data and not volume. The logbook was tested by trainees in several European training departments and adapted according to their suggestions. A final draft of the logbook was circulated among the national and professional societies for radiotherapy in Europe for review before a European consensus conference took place in Brussels in December 2002. RESULTS: The European training logbook for radiotherapy was endorsed by representatives of 35 European nations during the Brussels consensus conference on December 14, 2002. CONCLUSION: Keeping a training logbook is an essential feature of the record of training for all EU trainees who wish to retain an opportunity to spend part of their training time in another country of the Union, important for someone who seeks an appointment as a specialist in another country within a few years of achieving specialist accreditation, and good professional practice for all other trainees. The European training logbook for radiotherapy is a robust instrument that allows the systematic collection of the information that needs to be recorded to monitor the professional development of European trainees in Radiation Oncology.

Measurements of hypoxia using pimonidazole and polarographic oxygen-sensitive electrodes in human cervix carcinomas.

BACKGROUND AND PURPOSE: The measurement of tumour oxygenation using Eppendorf oxygen-sensitive needle electrodes can provide prognostic information but the method is limited to accessible tumours that are suitable for electrode insertion. In this paper the aim was to study the relationship between such physiological measurements of tumour hypoxia and the labelling of tumours with the hypoxia-specific marker pimonidazole. MATERIALS AND METHODS: Assessment of tumour oxygen partial pressure (pO(2)) using an Eppendorf pO(2) histograph and immunohistochemical pimonidazole labelling was carried out in 86 patients with primary cervix carcinomas. Pimonidazole was given as a single injection (0.5 g/m(2) i.v.) and 10-24 h later pO(2) measurements were made and biopsies taken. Tumour oxygenation status was evaluated as the median tumour pO(2) and the fraction of pO(2) values

Differential expression of cytokine genes in fibroblasts derived from skin biopsies of patients who developed minimal or severe normal tissue damage after radiotherapy.

Curative radiotherapy for cancer patients requires the use of radiation doses that are limited by the tolerance of the surrounding normal tissues. Unfortunately, these tolerance doses vary not only between tissues but also between individuals. In a small proportion of sensitive patients, exposure to radiation can lead to severe irreversible morbidity and even death several months to years after treatment. At present these radiosensitive patients can be identified only retrospectively. Here we describe a cytokine microarray technique that was used to identify differentially expressed gene transcripts in fibroblasts obtained from a small group of patients who suffered either negligible or severe normal damage to tissues after radiotherapy. If our preliminary findings can be confirmed, the availability of such markers may eventually allow the prediction of outcome prior to commencement of radiotherapy, and thus allow modification of radiotherapy protocols to minimize adverse late effects, without compromising tumor control.