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).

Autologous lymphocytes inhibit hemopoiesis in long-term culture in patients with myelodysplastic syndrome.

OBJECTIVE: The current therapy of myelodysplastic syndrome (MDS) is unsatisfactory and comprises mainly supportive treatment or antileukemic chemotherapy. Recent studies about successful immunosuppressive therapy suggest an autoimmune mechanism in subtypes of myelodysplastic syndrome. PATIENTS AND METHODS: To investigate this hypothesis, bone marrow mononuclear cells (MNC) from 15 patients with low-grade MDS, refractory anemia, and refractory anemia with ringed sideroblasts (RA and RARS), and from 7 normal donors were depleted of CD2(+), CD5(+), and CD7(+) lymphocytes using magnetic cell sorting. Depleted and nondepleted MNC were seeded onto irradiated allogeneic bone marrow stroma and the generation of colony-forming-cells (CFC), the clonal origin of hemopoietic progenitor cells in long-term bone marrow culture (LTC), was compared. RESULTS: The capacity of MNC from 7 healthy donors to generate hemopoiesis remained unchanged in the lymphocyte-depleted LTC. In contrast, cultures initiated with lymphocyte-depleted MNC from patients with RA and RARS exhibited a significantly increased generation of CFC compared with the corresponding nondepleted cultures. Microsatellite analysis in 6 patients revealed that a significantly increased number of CFC grown in lymphocyte-depleted LTC showed no allelic loss, suggesting an outgrowth of normal hemopoietic cells. CONCLUSION: These results provide a rationale for the recently described successful treatment of MDS with immunosuppressive therapy. We suggest that in certain subtypes of MDS the residual normal hemopoiesis is suppressed by autoimmune mechanisms, eventually allowing the expansion of the abnormal clone.

Short course para-aortic radiation for stage I seminoma of the testis.

PURPOSE: To determine the outcome in men with Stage I seminoma treated with low-dose para-aortic radiation. MATERIALS AND METHODS: Between January 1988 and December 2000, 431 men with Stage I seminoma were treated with para-aortic radiation to a midplane dose of 20 Gy in 8 fractions over 10 days. RESULTS: At a median follow-up of 62 months, 15 patients (3.5%) had relapsed, with a median time to relapse of 13 months (range: 9 to 39 months). Nine patients had pelvic nodal relapse; in addition, 1 patient had para-aortic involvement, and 2 had distant disease. Four had metastatic disease only (mediastinum 2, lung 2). One patient had scrotal recurrence, and 1 was treated for progressive rise in human chorionic gonadotrophin without identifiable disease. Initial treatment at relapse was chemotherapy (12), radiation (2), and surgery (1). One patient died from progressive disease. Thirteen men (3%) have developed second malignancies, including 7 contralateral testicular tumors, 5 solid malignancies, and 1 leukemia. The overall 5-year survival was 98%, and the estimated recurrence-free survival at 5 years was 96.3%. On log-rank univariate analysis, lymphovascular invasion, involvement of the tunica, and a preoperative human chorionic gonadotrophin level of greater than 5 were found to be of prognostic significance for recurrence. CONCLUSIONS: These data support short-duration, limited-field radiation as an optimal safe and effective protocol in the management of Stage I seminoma patients.

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.

FGFR2, HER2 and cMet in gastric adenocarcinoma: detection, prognostic significance and assessment of downstream pathway activation.

Receptor tyrosine kinase pathways are potential therapeutic targets in gastric adenocarcinoma patients. We evaluated HER2 and cMet protein expression, and FGFR2 gene amplification to assess their prognostic significance, and downstream mediators pS6 and pERK for their potential utility as pharmacodynamic biomarkers in patients with gastric adenocarcinoma. Tissue microarrays were constructed from resection samples of 184 patients who underwent surgery for gastric/gastro-oesophageal junction adenocarcinoma. Tissue cores were obtained from the tumour body (TB), luminal surface (LS) and invasive edge (IE), and immunohistochemical and fluorescence in situ hybridisation (FGFR2) analysis was performed. FGFR2 amplification was identified in 2 % of cases and associated with worse survival (P = 0.005). HER2 overexpression was observed in 10 % of cases and associated with increased survival (P = 0.041). cMet overexpression was observed in 4 % of cases and associated with worse survival (P < 0.001). On multivariate analysis, only cMet retained significance (P = 0.006). pS6 and pERK expression were observed in 73 % and 30 % of tumours, respectively, with no association with survival. HER2 (P = 0.004) and pERK (P = 0.001) expression differed between tumour regions with HER2 expression increased in the LS compared with the TB and IE. These findings confirm subpopulations in gastric adenocarcinoma with poor outcome that may benefit from specific therapeutic strategies. However, we found heterogeneous HER2, pS6 and pERK overexpression, which presents challenges for their use as predictive biomarkers in gastric biopsies. The potential downstream pharmacodynamic markers pS6 and pERK were expressed across tumour regions, providing evidence that resections and biopsies would yield comparative results in clinical trials.

Telomere length dynamics differ in foetal and early post-natal human leukocytes in a longitudinal study.

Haemopoietic stem cells (HSC) undergo a process of self renewal to constantly maintain blood cell turnover. However, it has become apparent that adult HSC lose their self-renewal ability with age. Telomere shortening in peripheral blood leukocytes has been seen to occur with age and it has been associated with loss of HSC proliferative capacity and cellular ageing. In contrast foetal HSC are known to have greater proliferative capacity than post-natal stem cells. However it is unknown whether they undergo a similar process of telomere shortening. In this study we show a more accentuated rate of telomere loss in leukocytes from pre term infants compared to human foetuses of comparable age followed longitudinally for 8-12 weeks in a longitudinal study. Our results point to a difference in HSC behaviour between foetal and early postnatal life which is independent of age but may be influenced by events at birth itself.