The presenting clinical features of 71 patients with multiple myeloma were correlated with myeloma cell mass (myeloma cells X 10(12)/m2 of body surface area) determined from measurements of monoclonal immunoglobulin (M-component) synthesis and metabolism. Bivariate correlation and multivariate regression analyses showed that myeloma cell mass could be accurately predicted from A) extent of bone lesions, B) hemoglobin level, C) serum calcium level, and D) M-component levels in serum and urine. Analyses of response to chemotherapy and survival indicated significant correlation with measured myeloma cell burden. The results were synthesized to produce a very reliable and useful clinical staging system with three tumor cell mass levels (Table 7). For clinical research purposes, multivariate regression equations were developed to predict optimally the exact myeloma cell mass. Thus, initial staging can be quantitatively related to followup using tumor cell mass changes calculated from changes in M-component production. Use of the clinical staging system sould provide better initial assessment and followup of individual patients, and should lead to improved study design and analysis in large clinical trials of therapy for multiple myeloma.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/1097-0142%28197509%2936%3A3%3C842%3A%3AAID-CNCR2820360303%3E3.0.CO%3B2-U

A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival

The following diagnostic criteria are proposed to classify four clinical subtypes of HTLV-1 associated adult T-cell leukaemia-lymphoma (ATL): (1) Smouldering type, 5% or more abnormal lymphocytes of T-cell nature in PB, normal lymphocyte level (less than 4 x 10(9)/l), no hypercalcaemia (corrected calcium level less than 2.74 mmol/l), lactate dehydrogenase (LDH) value of up to 1.5 x the normal upper limit, no lymphadenopathy, no involvement of liver, spleen, central nervous system (CNS), bone and gastrointestinal tract, and neither ascites nor pleural effusion. Skin and pulmonary lesion(s) may be present. In case of less than 5% abnormal T-lymphocytes in PB, at least one of histologically-proven skin and pulmonary lesions should be present. (2) Chronic type, absolute lymphocytosis (4 x 10(9)/l or more) with T-lymphocytosis more than 3.5 x 10(9)/l, LDH value up to twice the normal upper limit, no hypercalcaemia, no involvement of CNS, bone and gastrointestinal tract, and neither ascites nor pleural effusion. Lymphadenopathy and involvement of liver, spleen, skin, and lung may be present, and 5% or more abnormal T-lymphocytes are seen in PB in most cases . (3) Lymphoma type, no lymphocytosis, 1% or less abnormal T-lymphocytes, and histologically-proven lymphadenopathy with or without extranodal lesions. (4) Acute type, remaining ATL patients who have usually leukaemic manifestation and tumour lesions, but are not classified as any of the three other types. A total of 818 ATL patients with a mean age of 57 years, newly diagnosed from 1983 to 1987, were analysed by this criteria. There were 448 males and 370 females, and 253 were still alive with a median follow-up time of 13.3 months from diagnosis, while 565 were dead with a median survival time (MST) of 5.4 months. MST was 6.2 months for acute type, 10.2 months for lymphoma type, 24.3 months for chronic type, and not yet reached for smouldering type. Projected 2- and 4-year survival rates were 16.7% and 5.0% for acute type, 21.3% and 5.7% for lymphoma type, 52.4% and 26.9% for chronic type, 77.7% and 62.8% for smouldering type, respectively. Distinct clinical features and laboratory findings of each clinical subtype are described.

Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemia-lymphoma. A report from the Lymphoma Study Group (1984-87).

Diogenes syndrome. A clinical study of gross neglect in old age.

Objectives: To identify evidence for the role of bisphosphonates in malignancy for the treatment of hypercalcaemia, prevention of skeletal morbidity and use in the adjuvant setting. To perform an economic review of current literature and model the cost effectiveness of bisphosphonates in the treatment of hypercalcaemia and prevention of skeletal morbidity Data sources: Electronic databases (1966-June 2001). Cochrane register. Pharmaceutical companies. Experts in the field. Handsearching of abstracts and leading oncology journals (1999-2001). Review methods: Two independent reviewers assessed studies for inclusion, according to predetermined criteria, and extracted relevant data. Overall event rates were pooled in a meta-analysis, odds ratios ( OR) were given with 95% confidence intervals (CI). Where data could not be combined, studies were reported individually and proportions compared using chi- squared analysis. Cost and cost-effectiveness were assessed by a decision analytic model comparing different bisphosphonate regimens for the treatment of hypercalcaemia; Markov models were employed to evaluate the use of bisphosphonates to prevent skeletal-related events (SRE) in patients with breast cancer and multiple myeloma. Results: For acute hypercalcaemia of malignancy, bisphosphonates normalised serum calcium in >70% of patients within 2-6 days. Pamidronate was more effective than control, etidronate, mithramycin and low-dose clodronate, but equal to high dose clodronate, in achieving normocalcaemia. Pamidronate prolongs ( doubles) the median time to relapse compared with clodronate or etidronate. For prevention of skeletal morbidity, bisphosphonates compared with placebo, significantly reduced the OR for fractures (OR [95% CI], vertebral, 0.69 [0.57-0.84], non-vertebral, 0.65 [0.54-0.79], combined, 0.65 [0.55-0.78]) radiotherapy 0.67 [0.57-0.79] and hypercalcaemia 0.54 [0.36-0.81] but not orthopaedic surgery 0.70 [0.46-1.05] or spinal cord compression 0.71 [0.47-1.08]. However, reduction in orthopaedic surgery was significant in studies that lasted over a year 0.59 [0.39-0.88]. Bisphosphonates significantly increased the time to first SRE but did not affect survival. Subanalyses were performed for disease groups, drugs and route of administration. Most evidence supports the use of intravenous aminobisphosphonates. For adjuvant use of bisphosphonates, Clodronate, given to patients with primary operable breast cancer and no metastatic disease, significantly reduced the number of patients developing bone metastases. This benefit was not maintained once regular administration had been discontinued. Two trials reported significant survival advantages in the treated groups. Bisphosphonates reduce the number of bone metastases in patients with both early and advanced breast cancer. Bisphosphonates are well tolerated with a low incidence of side-effects. Economic modelling showed that for acute hypercalcaemia, drugs with the longest cumulative duration of normocalcaemia were most cost-effective. Zoledronate 4 mg was the most costly, but most cost-effective treatment. For skeletal morbidity, Markov models estimated that the overall cost of bisphosphonate therapy to prevent an SRE was pound250 and pound1500 per event for patients with breast cancer and multiple myeloma, respectively. Bisphosphonate treatment is sometimes cost-saving in breast cancer patients where fractures are prevented. Conclusions: High dose aminobisphosphonates are most effective for the treatment of acute hypercalcaemia and delay time to relapse. Bisphosphonates significantly reduce SREs and delay the time to first SRE in patients with bony metastatic disease but do not affect survival. Benefit is demonstrated after administration for at least 6-12 months. The greatest body of evidence supports the use of intravenous aminobisphosphonates. Further evidence is required to support use in the adjuvant setting.

/pdf/a-systematic-review-of-the-role-of-bisphosphonates-in-o1merva1fv.pdf

A systematic review of the role of bisphosphonates in metastatic disease.

In a double-blind trial of vitamin D supplements in pregnant Asian women calciferol (ergocalciferol, 1000 IU/day) was administered to 59 women and placebo to 67 controls during the last trimester. The two groups had similar distributions of maternal age, height, parity, number of vegetarians, countries of origin, and sex and gestation of the infants. At entry to the trial maternal serum 25-hydroxy vitamin D (25-OHD) concentrations were low in both treatment and control groups and significantly lower in vegetarians than non-vegetarians. Mothers in the treatment group gained weight faster in the last trimester than those in the control group, and at term they and their infants all had adequate plasma 25-OHD concentrations, Mothers and infants in the control group, however, had low plasma concentrations of 25-OHD and calcium and raised plasma alkaline phosphatase (bone isoenzyme) activity. Five of these infants developed symptomatic hypocalcaemia. Almost twice as many infants in the control group were small for gestational age (29% v 15%), but there were no significant differences between the two groups of infants in antropometric measurements. Infants in the control group, however, had larger fontanelles, suggesting impaired ossification of the skull. Because of the benefits to mothers and infants in the treatment group and the absence of side effects, vitamin D supplements should be given to all pregnant Asian women in the United Kingdom.

https://www.bmj.com/content/bmj/280/6216/751.full.pdf

Vitamin D supplements in pregnant Asian women: effects on calcium status and fetal growth.

Two hundred consecutive specimens received in this laboratory for "liver function tests" showed a wide range of abnormal protein concentrations. Calcium concentration correlated closely with albumin (r = 0.867) but less closely with total protein (r = 0.682). A simple formula for adjusting calcium concentration was derived from the regression equation of calcium on albumin. Adjusted calcium = calcium - albumin + 4.0, where calcium is in mg/100 ml and albumin in g/100 ml.Low calcium concentrations were found in 49 (24.5%) and raised concentrations in six (3%) of the 200 blood specimens taken for liver function tests. After adjustment, the 95% limits of the observed range were identical with the 95% limits of the normal range determined in this laboratory. Unlike adjustments based on total protein or specific gravity, the adjustment on albumin in 39 specimens which showed hypergammaglobulinaemia on electrophoresis gave normal calcium concentrations.

https://www.bmj.com/content/bmj/4/5893/643.full.pdf

Interpretation of serum calcium in patients with abnormal serum proteins

Sa ,-Dr. I. M. Murray-Lyon and others (29 December, p. 770) report four cases of malignant carcinoid tumour with gangrene of the small intestine and discuss the cause of the ischaemic change. Vascular change with elastic tissue proliferation due to the presence of tumour-elastic vascular sclerosis -is favoured by Anthony and Drury,' while Dr. Murray-Lyon and his colleagues suggest that a combination of restriction of blood flow due to the presence of tumour tissue and the characteristic fibrotic reaction in the root of the mesentery may lead to thrombosis of the mesenteric vessels. The vessels in their four cases also showed elastic tissue proliferation but as the lumen was not strikingly narrowed this was considered unimportant. A case recently presented at this institute in an 83-year-old woman dying of peritonitis following gangrene of the small intestine due to thrombosis of the superior mesenteric artery as it passed through an isolated, well-defined (3 X 2 x 2 cm) secondary deposit of carcinoid tumour in the mesentery. The primary tumour, an ulcerated, raised area 7 cm in diameter, was in the gangrenous loop of the small bowel. A solitary metastasis, 2 cm in diameter, was present in the liver, but there had been no clinical evidence of carcinoid syndrome. Histological examination showed the wall of the superior mesenteric artery to be surrounded by tumour tissue with thrombus in the lumen. The wall itself showed proliferation of elastic tissue but the lumen was not narrowed. The thrombus was confined macroscopically to the area running through the tumour deposit. Mesenteric fibrosis was not seen macroscopically. In the primary tumour the vessels, both arteries and veins, also showed proliferation of the elastica without marked narrowing of the lumen. This is in contrast to the case reported by Anthony and Drury,' in which such vessels were reported as near normal. In the veins these changes were accompanied by tumour cell infiltration and thrombosis.

https://www.bmj.com/content/bmj/1/5904/393.4.full.pdf

Letter: Correction of plasma calcium measurements.

walls of which, though distended, can be advanced caudally and united to the perineum.1 The use of a free skin graft to line a pocket newly created between the bladder and rectum may be a simple procedure but an annular construction often develops at the site of union between the graft and vaginal epithelium, which necessitates the frequent use of moulds in order to retain vaginal patency. Secondly, in the absence of a functioning uterus Williams's vulvovagino,Dlasty,2 a form of long perineorrhaphy, is particularly easy to perform. The operation is not only brilliantly simple in design but healing usually occurs quickly and without the troublesome formation of postoperative granulation tissue. As soon as the perineal skin is united the new vouch is immediately functional as a vagina. It does not depend for its patency upon coitus or the insertion of vaginal moulds. Any anatomical disadvantages which may attend vulvovaginoplasty are more theoretical than practical and are perhaps quite overshadowed by the singular advantage of the operation-namely, that it may safely be performed at a time which will assist the natural sociosexual development of the teenager. Free skin graft procedures, though reFulting in a normally situated vagina, are best deferred until regular coitus is expected; otherwise vaginal patency must be mnaintained by the regular use of dilators, instruments which sometimes Ferve chiefly to remind the young female of her fundamental abnormality as a woman. While accepting Mr. Cobbett's comment that the use of a free skin graft to line a newly created pocket is a simple operation, I submit that in amenorrhoeic women a vulvovaginoplasty is simpler and preferable and that in Datients with a functioning uterus advancement of the vagina is probably the treatment of choice.-I am, ec.,

https://www.bmj.com/content/bmj/3/5926/345.1.full.pdf

J. R. Milner

Papers

Interpretation of serum calcium in patients with abnormal serum proteins

Letter: Correction of plasma calcium measurements.

Letter: Adjustment of plasma calcium measurements.