Long-Term Follow-up of the Apparently Normal Couple with a Complaint of Infertility**Supported by a grant from the Medical Research Council, London (to E. A. L.).

Abstract Introduction: With conventional therapy, the median survival for patients following diagnosis of multiple myeloma (MM) is 31 months. Prior to 1985 2–4% of patients survived up to 10 years, subsequently this figure has improved to around 10%. We have analysed the United Kingdom Medical Research Council (MRC) trial records to identify the proportion, presentation features and outcome of patients who have survived greater than 7.5 years. Methods: Patients selected were those randomised to conventional (melphalan and ABCM based) therapy who survived greater than 7.5 years; all of these patients had achieved a plateau phase. Their presenting clinical and laboratory features were compared to a group of patients (matched by trial and treatment) who also reached plateau but were the first of the cohort to die directly from MM. Time to response and absolute response was calculated. Clinical course and performance status were assessed from 3 month follow-up clinical data forms and central laboratory paraprotein analysis. Results: 239/2781 (8.5%) of eligible patients survived greater than 7.5 years. 170 patients had died (median and interquartile range (IQR) 9.5 years and 8.3–11.7 years) and 69 patients were still alive at the time of the analysis, median follow-up of 11.4 years (IQR 9.2–14.1 years). Compared to the matched short-lived control group, these long term survivors had lower β2-microglobulin, preserved albumin, lower marrow plasmacytosis, less renal impairment, better performance status, fewer fractures, less bone pain and fewer lytic lesions at presentation. There were no differences in age, lymphocytes, or depth of serological response, however, median time to reach plateau was delayed for the long term survivors {0.77 years (IQR 0.41–1.05) versus 0.42 years (0.26–0.73 for controls)}. 35 patients remain in first plateau with no progression, 28 patients died in first plateau most commonly of vascular disease (25%) or cancer (21%). 176 patients relapsed and 11 (6%) died of myeloma in first relapse, however the majority (140/176, 80%) achieved a second plateau and having relapsed a second time 53/114 (46%) achieved a third plateau. 43 of these 140 patients died in second plateau or beyond of a cause other than myeloma - (vascular 7/43 (16%), cancer 5/43 (12%), renal 5/43 (12%), infection 6/43 (14%), other 4/43 (9%). 30/239 patients (13%) died with no information on disease status or cause of death. Following second relapse 73/114 (64%) patients died directly as a result of myeloma. Time spent in performance status 1 and 2 was 96% for plateau 1, 83% for relapse 1 and 63% beyond relapse 2. Conclusions: 8.5% of MRC trial patients receiving conventional non-intensive therapy survive greater than 7.5 years. Factors associated with long survival include low disease burden, better performance status and less end organ damage. Absolute serological response had no bearing on overall outcome; however rapid response is associated with poorer survival. The existence of second and subsequent plateau phases of MM, have rarely been documented in the literature. A large proportion of time following relapse is spent with good performance status, suggesting that patients experience a good quality of life during much of this period.

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Medical Research Council Clinical Psychiatry Unit

Psychological Medicine ◽

10.1017/s0033291700044822 ◽

1971 ◽

Vol 1 (5) ◽

pp. 429-436 ◽

Cited By ~ 1

Keyword(s):

Clinical Research ◽

Medical Research ◽

Research Council ◽

Medical Research Council ◽

County Council ◽

Regional Hospital ◽

Sussex County ◽

Hospital Boards ◽

Further Development

The Clinical Research Department was started at Graylingwell Hospital, Chichester, Sussex, by Dr. J. Carse in 1947, when the hospital was administered by Sussex County Council. The first director was Dr. (now Professor) E. Stengel, and he undertook the first systematic follow-up of leucotomized patients. From 1950 to 1955 the director was Dr. Martin Roth; his studies on the psychoses of old age, and especially those delineating depressive psychoses, are now a landmark in clinical research. At about this time, the means by which clinical research in the National Health Service hospitals should be administered was reviewed and a policy evolved whereby departments in which clinical research was prospering and whose further development would make financial demands beyond those available to the regional hospital boards would be considered for support by the Medical Research Council.

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Short-course adjuvant chemotherapy in high-risk stage I nonseminomatous germ cell tumors of the testis: a Medical Research Council report.

Journal of Clinical Oncology ◽

10.1200/jco.1996.14.4.1106 ◽

1996 ◽

Vol 14 (4) ◽

pp. 1106-1113 ◽

Cited By ~ 238

Author(s):

M H Cullen ◽

S P Stenning ◽

M C Parkinson ◽

S D Fossa ◽

S B Kaye ◽

...

Keyword(s):

High Risk ◽

Adjuvant Chemotherapy ◽

Germ Cell ◽

Medical Research ◽

Research Council ◽

Medical Research Council ◽

Germ Cell Tumors ◽

Stage I ◽

Nonseminomatous Germ Cell Tumors

PURPOSE This United Kingdom Medical Research Council (UK-MRC) study prospectively evaluated efficacy and long-term toxicity of adjuvant chemotherapy in high-risk stage I nonseminomatous germ cell tumors of the testis (NSGCTT). PATIENTS AND METHODS Eligible patients were those identified by the local histopathologist as having features confirmed in MRC surveillance studies to indicate an approximate 50% risk of relapse. Central histopathology review was undertaken. Chemotherapy consisted of two courses of cisplatin 100 mg/m2, bleomycin 30 mg weekly x 3, and etoposide 120 mg/m2 x 3, every 21 days (BEP). RESULTS One hundred fourteen eligible cases were enrolled. Median time of follow-up was 4 years, with 93 patients followed-up for at least 2 years. There have been two relapses, including one patient who did not have a germ cell tumor (GCT), according to the reference histopathologist. This patient is alive with active disease, the other has died. There was one death after a cerebrovascular accident during treatment. Assessment of fertility, lung function, and audiometry pretreatment and more than 9 months posttreatment indicated no clinically significant changes. A mean decrease in transfer factor coefficient (KCO) of 15% of the predicted value was noted, but no patient had symptomatic respiratory dysfunction. CONCLUSION There have been only two relapses among 114 cases of high-risk stage I NSGCTT treated with two courses of adjuvant BEP chemotherapy. The 95% confidence interval (CI) excludes a true relapse rate of more than 5%. Of 104 patients confirmed on histopathology review to have GCT, there has been only one relapse. Adjuvant chemotherapy is free from significant long-term toxicity, offering an effective alternative to surveillance or retroperitoneal lymph node dissection (RPLND) followed by surveillance, and may be preferred by some patients.

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Langzeit-Follow-up der Medical Research Council CLASICC-Studie von konventioneller vs. laparoskopisch assistierter Resektion beim kolorektalen Karzinom

coloproctology ◽

10.1007/s00053-014-0450-0 ◽

2014 ◽

Vol 36 (3) ◽

pp. 209-210

Author(s):

A. Fürst

Keyword(s):

Medical Research ◽

Research Council ◽

Medical Research Council

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Effects of induction and maintenance plus long-term bisphosphonates on bone disease in patients with multiple myeloma: the Medical Research Council Myeloma IX Trial

Blood ◽

10.1182/blood-2011-11-392522 ◽

2012 ◽

Vol 119 (23) ◽

pp. 5374-5383 ◽

Cited By ~ 88

Author(s):

Gareth J. Morgan ◽

Faith E. Davies ◽

Walter M. Gregory ◽

Alex J. Szubert ◽

Sue E. Bell ◽

...

Keyword(s):

Multiple Myeloma ◽

Medical Research ◽

Bone Disease ◽

Research Council ◽

Medical Research Council ◽

Newly Diagnosed ◽

Treatment Pathways ◽

Skeletal Related Event ◽

Oral Clodronate

AbstractThe Medical Research Council Myeloma IX Trial (ISRCTNG8454111) examined traditional and thalidomide-based induction and maintenance regimens and IV zoledronic acid (ZOL) and oral clodronate (CLO) in 1960 patients with newly diagnosed multiple myeloma. Overall survival (OS) and skeletal-related event (SRE) data have been reported for the overall trial population. The present analysis investigated optimal therapy regimens for different patient populations in Myeloma IX. Patients were assigned to intensive or nonintensive treatment pathways and randomized to induction cyclophosphamide, vincristine, doxorubicin, and dexamethasone (CVAD) versus cyclophosphamide, thalidomide, and dexamethasone (CTD; intensive) or melphalan and prednisolone versus attenuated oral CTD (CTDa; nonintensive). Patients were also randomized to ZOL or CLO. In the nonintensive pathway, CTDa produced better responses and lower SRE rates than melphalan and prednisolone. ZOL improved OS compared with CLO independently of sex, stage, or myeloma subtype, most profoundly in patients with baseline bone disease or other SREs. In patients treated for ≥ 2 years, ZOL improved OS compared with CLO from randomization (median not reached for either; P = .02) and also from first on-study disease progression (median, 34 months for ZOL vs 27 months for CLO; P = .03). Thalidomide-containing regimens had better efficacy than traditional regimens, and ZOL demonstrated greater benefits than CLO.

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Retinal microvasculature and time to pregnancy in a multi-ethnic pre-conception cohort in Singapore

Human Reproduction ◽

10.1093/humrep/deab197 ◽

2021 ◽

Author(s):

Lihua Huang ◽

See Ling Loy ◽

Wei-Qing Chen ◽

Johan G Eriksson ◽

Yap Seng Chong ◽

...

Keyword(s):

Fractal Dimension ◽

Medical Research ◽

Research Council ◽

Medical Research Council ◽

Time To Pregnancy ◽

National Medical ◽

Retinal Microvasculature ◽

Branching Angle ◽

Retinal Arteriolar

Abstract STUDY QUESTION Can abnormalities in retinal microvasculature representing adverse microcirculatory perfusion and inflammation shed light on the pathophysiology of female fecundability? SUMMARY ANSWER In our prospective study, abnormalities in retinal vascular geometric morphology (i.e. sparser arteriolar fractal and larger venular bifurcation) during pre-conception phase are temporarily associated with a prolonged time-to-pregnancy (TTP). WHAT IS KNOWN ALREADY Suboptimal retinal microcirculatory morphology has been associated with obesity, psychological stress and hypertension, all of which are known risk factors for reduced female fecundability. STUDY DESIGN, SIZE, DURATION A total of 652 women of Chinese, Malay or Indian ethnicity 18–45 years of age and planning to conceive spontaneously within the next 12 months were recruited during the pre-conception period into the Singapore PREconception Study of long-Term maternal and child Outcomes (S-PRESTO), from February 2015 to October 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS During recruitment, we collected information on socio-demographic factors, menstrual characteristics and lifestyle behaviors and made anthropometric measurements. We assessed the following retinal microvascular features: caliber, branching angle and fractal dimension. We conducted follow-up telephone surveys to track each participant’s pregnancy status at 6, 9 and 12 months after enrolment. We ascertained clinical pregnancies via ultrasonography, with TTP measured by the number of menstrual cycles required to achieve a clinical pregnancy over a 1-year follow-up. Then, we performed discrete-time proportional hazards models to estimate the fecundability odds ratio (FOR) and 95% CI for each retinal microvascular feature in association with TTP, after adjusting for major confounders, including body mass index and fasting glycemic level at study entry. MAIN RESULTS AND THE ROLE OF THE CHANCE Among 652 recruited women, 276 (42.3%) successfully conceived within 1 year of follow-up. The mean (and SD) was 1.24 (0.05) Df for retinal arteriolar dimension fraction and 78.45 (9.79) degrees for retinal venular branching angle, respectively. Non-linear relationship testing was performed before multiple adjustment in all associations and a non-monotonic association was detected between retinal venular branching angle and TTP. Compared with women in the highest tertile of retinal arteriolar fractal dimension, women in the second tertile had a prolonged TTP (FOR: 0.68; 95% CI: 0.51–0.92), as did women in the lowest tertile (FOR: 0.73; 95% CI: 0.55–0.98). Compared with women in the middle tertile of retinal venular branching angle, women in the highest tertile had a borderline prolonged TTP (FOR: 0.75; 95% CI: 0.56–1.02). No other retinal vascular features were significantly associated with TTP. LIMITATIONS, REASONS FOR CAUTION We were unable to adjust for other potential confounding factors such as female sexual function (e.g. frequency of sexual intercourse), which might introduce a residual bias. Moreover, even though this is a prospective cohort design, our findings can identify the temporal relationship but not necessarily infer a causal relationship between maternal microvasculature and TTP. Lastly, our study involving mainly Chinese, Malay and Indian ethnicities might not be generalizable to other races or ethnicities. WIDER IMPLICATIONS OF THE FINDINGS Suboptimal microcirculation may lead to reduced female fecundability. In the future, in addition to conventional ultrasonographic evaluation of ovarian and uterine physiological function, assessing the retinal microvasculature might be useful for assessment of ovarian age, fertility prediction and endometrial evaluation before assisted reproductive techniques for fertility treatments. STUDY FUNDING/COMPETING INTEREST(S) This research is supported by the Singapore National Research Foundation (NRF) under its Translational and Clinical Research (TCR) Flagship Programme and administered by the Singapore Ministry of Health’s National Medical Research Council (NMRC) (Singapore-NMRC/TCR/004-NUS/2008; NMRC/TCR/012-NUHS/2014) and Singapore National Medical Research Council Transition Award (NMRC TA/0027/2014). The authors have no competing interests to declare. TRIAL REGISTRATION NUMBER ClinicalTrials.gov, NCT03531658.

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