We have used immunohistochemical staining to assess the expression of cyclin D I in formalin-fixed sections of 345 breast carcinomas, dating back 20 years. Clinical follow-up data were available on all patients. Approximately 50% of the tumours showed excessive nuclear staining for cyclin DI as compared with normal epithelium. Some tumours showed strong cytoplas-mic staining in the absence of nuclear staining, and around 25% of the tumours were judged to be negative for nuclear cyclin D I. Contrary to expectations, moderate/strong staining for cyclin D I was associated with improved relapse-free and overall survival relative to patients whose tumours stained weakly or negatively. Conversely, tumours that were considered negative for cyclin DI staining had an adverse prognosis, and the poor outcome was further accentuated if the tumours were also oestrogen receptor-negative. A possible explanation for our findings is that tumours in which cyclin D I levels are abnormally low may have sustained mutations in other genes, such as R 6 I and that it is this abnormality that has the more significant impact on survival from breast cancer. 8 1996 Wiley-Liss, Inc.

Summary Three hundred and sixty-seven women presenting to the Breast Unit at Guy's Hospital between 1975 and 1990 whose first distant metastasis was in the skeleton were identified and the influence of a number of patient and tumour characteristics on the development and subsequent prognosis of bone metastases was assessed.One hundred and thirty-nine women had disease that remained clinically confined to the skeleton. They were more likely to be older, with lobular carcinoma and to have presented initially with little or no axillary lymph node involvement. The 228 women who subsequently developed disease at extra-osseus sites were more likely to have poorly differentiated ductal tumours and heavy lymph node involvement at primary diagnosis.On multivariate analysis, the clinical and pathological factors of greatest prognostic importance for survival after the development of bone metastases were histological grade (P = < 0.0001), oestrogen receptor status (P = < 0.0001), bone disease at initial presentation (P= < 0.0001), disease-free interval (P= 0.002) and age (P= 0.006).To enable a rational cost-effective use of bisphosphonates in metastatic bone disease, selection of patients with relatively indolent, bone-only disease for bisphosphonate therapy (as defined in this study) should be compared with the current licensed recommendation of unselected treatment for all patients with lytic bone metastases.Bone metastases are frequent in advanced breast cancer and often contribute to the cause of death. Like breast cancer affecting other organs, metastatic bone disease has an extremely variable prognosis. The median survival is 2 years with 20% of patients remaining alive for 5 years after first recurrence in bone (Coleman and Rubens, 1987). In addition, a significant proportion of patients appear clinically to have disease confined to the skeleton, and these women die of the complications of metastatic bone disease, namely immobility, pathological fractures, hypercalcaemia of malignancy and bone marrow failure, with no evidence clinically of involvement at other metastatic sites.With the development of bisphosphonates as specific treatments for metastatic bone disease (Body et al, 1996), there is increased interest in identifying those patients who are most likely to benefit from bisphosphonate treatment. In addition, if prophylactic use of bisphosphonates proves able to influence the development of bone metastases, it will be important to identify those patients at greatest risk of bone involvement, particularly in isolation from other metastatic disease, so that treatment can be targeted rationally. In this study, we have reviewed the clinical and tumour characteristics of patients developing first recurrence of breast cancer in bone and identified prognostic factors that predict for both survival and/or subsequent spread to other metastatic sites. PATIENTS AND METHODSThree hundred and sixty-seven women presenting to the Breast Unit at Guy's Hospital between 1975 and 1990 whose first distant metastasis was in the s...

Writing Committee for the REMAP-CAP Investigators IMPORTANCE The evidence for benefit of convalescent plasma for critically ill patients with COVID-19 is inconclusive.OBJECTIVE To determine whether convalescent plasma would improve outcomes for critically ill adults with COVID-19. DESIGN, SETTING, AND PARTICIPANTSThe ongoing Randomized, Embedded, Multifactorial, Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) enrolled and randomized 4763 adults with suspected or confirmed COVID-19 between March 9, 2020, and January 18, 2021, within at least 1 domain; 2011 critically ill adults were randomized to open-label interventions in the immunoglobulin domain at 129 sites in 4 countries. Follow-up ended on April 19, 2021. INTERVENTIONSThe immunoglobulin domain randomized participants to receive 2 units of high-titer, ABO-compatible convalescent plasma (total volume of 550 mL ± 150 mL) within 48 hours of randomization (n = 1084) or no convalescent plasma (n = 916). MAIN OUTCOMES AND MEASURESThe primary ordinal end point was organ support-free days (days alive and free of intensive care unit-based organ support) up to day 21 (range, −1 to 21 days; patients who died were assigned -1 day). The primary analysis was an adjusted bayesian cumulative logistic model. Superiority was defined as the posterior probability of an odds ratio (OR) greater than 1 (threshold for trial conclusion of superiority >99%). Futility was defined as the posterior probability of an OR less than 1.2 (threshold for trial conclusion of futility >95%). An OR greater than 1 represented improved survival, more organ support-free days, or both. The prespecified secondary outcomes included in-hospital survival; 28-day survival; 90-day survival; respiratory support-free days; cardiovascular support-free days; progression to invasive mechanical ventilation, extracorporeal mechanical oxygenation, or death; intensive care unit length of stay; hospital length of stay; World Health Organization ordinal scale score at day 14; venous thromboembolic events at 90 days; and serious adverse events. RESULTS Among the 2011 participants who were randomized (median age, 61 [IQR, 52 to 70] years and 645/1998 [32.3%] women), 1990 (99%) completed the trial. The convalescent plasma intervention was stopped after the prespecified criterion for futility was met. The median number of organ support-free days was 0 (IQR, -1 to 16) in the convalescent plasma group and 3 (IQR, -1 to 16) in the no convalescent plasma group. The in-hospital mortality rate was 37.3% (401/1075) for the convalescent plasma group and 38.4% (347/904) for the no convalescent plasma group and the median number of days alive and free of organ support was 14 (IQR, 3 to 18) and 14 (IQR, 7 to 18), respectively. The median-adjusted OR was 0.97 (95% credible interval, 0.83 to 1.15) and the posterior probability of futility (OR <1.2) was 99.4% for the convalescent plasma group compared with the no convalescent plasma group. The treatment effects were consistent across the primary outcome and the 11...

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