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In the Edinburgh Breast Screening Project 210 cancers were detected from commencement in 1979 up to December, 1984. By this time the full initial cohort had completed at least 3 visits and a proportion had attended for up to 5 visits, so pathological characteristics for prevalent and incident cancers could be compared. The main differences are in distribution of histological type of cancer, detection of occult invasive disease, and lymph-node positivity among incident tumours. Only the first of these was statistically significant. This evaluation shows that cancer detection by screening in Edinburgh conforms with screening theory, in which detection of good prognosis tumours is favoured at the prevalence screens, and faster growing, aggressive tumours are found at the incidence screens. Qualitative histopathology may provide a better measure than standard quantitative judgments of size and lymph node status to compare the varieties of cancer detected by screening programmes and to understand the biology of the disease.

The ultrastructural characteristics of 14 cases of mucoid carcinoma of the breast, with different histological appearances, have been examined. Thirteen of the tumours were observed to consist of two populations of tumour cells, one showing secretory changes while the other group showed no evidence of activity. In one tumour only synthetically active cells were observed. Ultrastructurally, six different types of cytoplasmic granules, comprising typical mucin plus glycoprotein or protein-containing granules, were identified within the synthetically active tumour cells. The number of types of granules and the relative proportion of the various granules varied between tumours with only mucin granules present in all tumours. It would appear that synthetic pathways are activated in certain tumours which result in protein/glycoprotein granules associated with the argyrophilia observed histologically. In addition, the tumours varied with respect to luminal differentiation, presence of intracytoplasmic lumina, intracytoplasmic mucin pools, lipid droplets, ciliated cells and areas of calcification. The marked heterogeneity of the ultrastructural features of the mucoid carcinoma of the breast prevents the tumours from being readily divided into distinct subgroups.

An interactive graphics display system that allows users to display and to alter monoscopic or stereoscopic projections of crystallographic or quantum mechanical models and to communicate with a central computer facility is described. The display panel is a digital write-only memory plasma panel with a grid of 512 × 512 points; a mini-computer is used to drive the panel. The molecular graphics mode software has been written in BASIC with the addition of graphics—primitives that simplify the display of geometric figures. The communication mode software has been written in an assembler language routine that may be called from BASIC. The ASCII character code is presently used for communication through a 1200 baud modern to the central computer facility. Communications are effected in two modes. (1) Information from local files and the keyboard flow to the central facility and from there back to the plasma tube and local files; or (2) the graphics system and central facility appear as a two processor computer with programs cooperatively executing simultaneously on both central processors. A description of a minimal and expanded system is included. The relatively low cost of such a system suggests it is applicable to a number of limited budgets. The simplicity of the system makes it a valuable tool for teaching and research in crystallography, quantum mechanics, and topics of general chemical interest.

The Edinburgh Breast Screening Clinic in its first year completed the initial screening examination of 3005 invited women, who were apparently in good health, aged between 40 and 60 years; 141 were referred for a surgical opinion; 70 women ultimately underwent biopsy and 9 proved to have carcinoma. The indications for biopsy are described together with methods of management of the various lesions.

Cellular DNA was analysed by flow cytometry in fine needles aspirates (FNA) from both benign and malignant breast lesions in order to determine the feasibility of flow cytometric analysis. In 22 of 26 (84%) benign and 69 of 74 (93%) malignant aspirates, sufficient cells were present to produce good quality DNA histograms. DNA in all 22 benign lesions was diploid. In contrast, of the 69 cancers with sufficient cells for analysis, 40.6% had a diploid DNA content alone, whilst 59.4% had an additional DNA aneuploid line. These results indicate that the majority of FNAs provide sufficient material for flow cytometric analysis of DNA profiles. Such aspirates taken in a sequential manner may also prove to be an ideal method of studying tumour response to therapy.

Conventional therapy for leukemic meningitis includes cranial irradiation and intrathecal chemotherapy administered by repeated lumbar punctures or direct intraventricular instillation via an Ommaya reservoir. Several clinical reports have indicated that high doses of cytosine arabinoside (ara-C) are effective in the treatment of acute leukemia refractory to standard induction therapy. Pharmacokinetic studies have demonstrated that high doses of ara-C given intravenously obtain sustained therapeutic drug concentrations in the cerebrospinal fluid, suggesting that this approach may be useful in the treatment of systemic disease associated with meningeal involvement. Five consecutive patients with overt meningeal leukemia were treated using only systemic chemotherapy containing high-dose ara-C. In all patients there was prompt resolution of neurologic symptoms and signs accompanied by cytologic clearing of leukemic cells from the cerebrospinal fluid.

5-Fluorouracil (5FU) administered by prolonged intravenous infusion may more effectively treat advanced, slow-growing tumors with low growth fractions and long doubling times. Protracted infusion provides continual cancer cell exposure to 5FU; limitations due to cell cycle specificity and a short plasma half-life are theoretically circumvented. Advances in catheter composition and pump technology now make ambulatory infusion therapy widely available. Clinical trials suggest that prolonged infusion may improve the response rate in colorectal cancer. In addition, preliminary results suggest clinical activity against gastric, pancreatic and refractory breast cancers with minimal toxicity. Despite the potential logistic problems of infusion chemotherapy, many patients report improved quality of life. Increased costs incurred from infusion therapy are probably justifiable if survival is prolonged and quality of life maintained.

Between 1980 and 1983, 689 women with primary breast cancer at the Royal Infirmary of Edinburgh and associated Hospitals had fine-needle aspiration biopsies prior to definitive surgery. Clinical factors relating to the success of these aspirations were evaluated. The most significant factor was which physician performed the aspiration. Size of the lesion was also an important variable; however, size difference could not account for the marked variation between different individuals performing the aspiration. There was no difference between node-positive and node-negative patients when matched by tumor size. A significantly lower rate of positive aspirations occurred in the 45 to 55 year age group which could not be accounted for by tumor size. Location of the mass was not significant, although there was a persistent lower rate of positive aspirates from the upper inner quadrants. Aspiration cytology was positive or suspicious in 65 percent of patients with primary breast cancer who had clinical diagnoses of benign breast lesions. It is concluded that the most significant variable in the accuracy of breast aspiration biopsy is the size of the lesion and the proficiency of the individual performing the procedure. With a skilled physician, positive aspiration results were obtained in over 80% of breast cancers.

Edinburgh was selected as one of the centres in the UK Seven-year Trial of Breast Screening of women aged 45-65 which began in 1979. Subsequently, our study was extended to a randomised trial with its own control population within the city. Half the practices were randomly allocated for screening, giving a cluster sampling of women. The total number in the trial is 65,000. Women with previously diagnosed breast cancer are excluded. Women allocated for screening are invited to the clinic and screened according to the procedures specified in the U.K. protocol, having clinical examination every year and mammography on alternate years. The two modalities of screening are assessed independently and the role of nurses is being evaluated. Breast cancer incidence is monitored by pathology register and the local cancer registry office and deaths from the General Register office. Long-term follow-up will be obtained through flagging at NHS Central Register. To determine the value of screening, standard statistical methods will be used to compare breast cancer mortality rates in the whole of the screening population with that of the controls. This trial has a power of 83% of detecting a reduction in mortality of 35% after 7 years of follow-up and a power of 95% of detecting a similar reduction at 10 years (alpha = 0.05, one-sided test).

The clinical and pathologic features of five cases of a previously poorly defined syndrome, benign mesothelial proliferation with effusion, are described. Although this is a benign process, both the gross and the microscopic findings may mimic metastatic papillary adenocarcinoma. Three of five patients had dysynchronous Involvement in more than one body cavity developing over intervals of one, two, and six years. The clinical course is unpredictable and is usually associated with a good prognosis, but two of three patients with pericardial involvement required pericardectomy for pericardial tamponade. The entity of benign mesothelial proliferation with effusion and its distinction from true malignant conditions are discussed.

The crystal and molecular structure determinations of 2,2,4,4,6,6,8,8-octamethyl-2,4,6,8-tetrasila-1,5-mercuracyclooctane. Hg 2 Si 4 C 10 H 28 (I) and of bis-(triphenylsilyl)mercury, (Ph 3 Si) 2 Hg (II), are reported. The structures have been determined from single-crystal X-ray data collected by counter methods. Both molecules crystalize in the space group P 1 with one centrosymmetric molecule per unit cell. Each structure contains linear SiHgSi groups, with mercury-silicon distances of 2.490(4) A in I and 2.503(4) A II. In compound I the SiHgSi groups are linked by methylene bridges which form an eight member ring in the chair conformation. The cell dimensions for compound I are a 6.277(2), b 8.408(2), c 9.274(4) A, α 92.75(3), β 94.79(3) and γ 100.14(2)° with R 1 0.062 for 1809 observed reflections. The cell dimensions for compound II are a 9.999(4), b 11.727(8), c 7.654(5) A, α 99.87(5), β 115.35(4) and γ 98.41(4)°, with R 1 0.081 for 2394 observed reflections.

The chemistry of the colouring matters has, perhaps, scarcely as yet met with the extended and complete investigation which the importance of the subject, in a theoretical and practical point of view, appears to deserve. The attention of chemists has been almost exclusively directed to the study of a comparatively small number of these substances, such as indigo, logwood, and the colouring matters of the lichens, which have been well and completely investigated; while the remaining, and by far the more extensive class, has received only a very partial and imperfect examination. To the latter, however, belong some of the most important of our dyes; and among others, the most valuable and indispensable of all, madder namely, the chemistry of which forms a problem as yet very far from being solved, but which chemists have shewn little disposition to submit to a thorough and searching investigation; and this disinclination seems to continue, notwithstanding that ground has been broken on the subject by the important observations of Robiquet, Kuhlmann, Runge, and others, which, though extremely incomplete, serve at least to indicate the importance of the results it is likely to afford, and to clear away the preliminary difficulties by which the commencement of such an investigation is surrounded.

During the last few years, great progress has been made in the study of the organic alkalies, and the discovery of methods by which these substances can be artificially produced, and the long train of investigations by which it has been followed, has greatly extended our previous information, and afforded us some definite ideas regarding their constitution. The advance made has, however, related entirely to the volatile bases produced by artificial processes, and our knowledge of the natural fixed alkaloids stands very much where it did some years since, and is still very imperfect, and in regard to many entirely fragmentary; so much so, indeed, that of all the alkaloids of this class described in chemical works, there are not perhaps a dozen of which the constitution can be considered as definitely fixed, and not half that number of which we know the products of decomposition. The fact is, that the interest attaching to the artificial bases has altogether diverted the attention of chemists from the natural alkalies, which have not hitherto proved a very productive field of inquiry; at least the researches to which many of them were subjected ten or fifteen years since, proved comparatively unfruitful in their results.

The following pages are intended merely as a preliminary notice of an investigation, which has occupied me for some time past, and which, though still too incomplete for publication in full, is sufficiently advanced to render obvious the general character of the results, although, from the extensive and elaborate nature of the inquiry, a very considerable time must elapse before it is complete in all the requisite details.

The solid compounds of carbon and hydrogen form a class of substances to which chemists have scarcely, as yet, paid that attention which their importance and interest appear to merit. With the exception of naphthaline, very little is known regarding them, and it is remarkable that the numerous and varied products of decomposition obtained from that singular substance should not have induced a more minute examination of the kindred compounds, whose existence has been indicated by different chemists. The interest attaching to these compounds is all the greater because, according to their discoverers, several of them are isomeric, or at least polymeric, with naphthaline; and a more careful examination of them might be expected to throw some light on their intimate constitution, and relations to that body.

The minerals of the zeolite family have for many years attracted the especial attention of men of science, and the class has been rapidly extended in proportion to the progress made in its study in a crystallographic as well as chemical point of view. The first characteristic difference, originally observed long since by Cronstedt, and by him considered to be the distinguishing mark of one single mineral species, which he designated Zeolite,—namely, the property of swelling out by heat previous to fusion,—has since been found to belong to a great number of other combinations. These, although materially different from each other in crystallographic form, have proved to be closely allied in chemical constitution, in so far as they consist, without exception, of a silicate of an alkali or alkaline earth, in combination with a silicate of alumina and water. It is evident, then, that the relation of the silicic acid to the base, in both terms, as well as the quantity of water, is capable of considerable variation, so that the general niineralogical formula which should embrace all the members of the zeolite family would beWhere r represents the monatomic alkaline or earthy basis, and the terms u, t, ,T, y, and z, are capable of varying within certain limits.

Since the year 1803, when Desrone discovered the substance which afterwards received the name of Narcotine, the chemical investigation of opium has engaged the attention of many skilful and distinguished chemists, and in their hands has proved the source of a series of substances, unprecedented in their number and the variety of their properties. Up to the present time, there have been detected in it no less than eleven different substances, one acid, and ten, either basic or indifferent, all presenting definite characters and crystalline form, besides various imperfectly characterised substances, described under the names of caoutchouc of opium, resin of opium, extractive, and the like.

In pursuing the investigation of the crystalline constituents of opium, which formed the subject of a previous communication to this Society, I have succeeded in obtaining from the same mother liquor which formed the raw material of my previous researches, a considerable quantity of papaverine, the base recently detected by Merck, and of meconine, the indifferent crystallizable substance discovered by Couerbe in the year 1830. The former was encountered quite unexpectedly in the precipitate from which narcotine and thebaine were prepared by the process described in the first series of these researches. The latter was only obtained after many fruitless trials, in which I was induced to persevere by the desire of comparing it with the substance discovered by myself among the products of the decomposition of narcotine by nitric acid, and described under the name of opianyl. The composition of that substance, as determined by my analyses, approximates very closely to that of meconine; and though the formula assigned to the former is double that obtained by Couerbe from his analysis of the latter, the sole reason for adopting the higher atomic weight was, that the mode in which opianyl was obtained by the decomposition of narcotine, afforded satisfactory grounds for establishing its true constitution.

Numerous researches have established as a general rule that the products of the decomposition of organic substances vary with the circumstances of the experiment, and the nature of the agents under the influence of which it is performed. If, for instance, we examine the action of heat alone, we find it causing a set of decompositions specially characterised by the evolution of carbonic acid, formed by the union of part of the carbon of the substance with the whole or part of its oxygen; and this action is rendered more definite, and the number of the products circumscribed by all circumstances facilitating the formation of carbonic acid, such as the presence of a base, which will even cause its evolution when heat alone is incapable of producing decomposition. Acids, on the other hand, have a precisely opposite effect, they, in some instances, altogether prevent the formation of carbonic acid, and cause the oxygen to exert its action on the hydrogen of the compound, and to eliminate one or more atoms of water which do not generally exist ready formed in it.

Owing to the great length of time over which the investigation of the products of the destructive distillation of animal substances has stretched, and various circumstances which it is unnecessary to detail, the inquiry has been pursued in a somewhat fragmentary manner, and with less continuity than might have been desired. The difficulties attending many of the experiments, and the occasional exhaustion of materials prepared by laborious processes, extending in many instances over considerable periods, have occasioned long intervals in the regular course of the inquiry which it became necessary to occupy with the examination of such matters as could be taken up at the moment. In this way a number of facts required to complete the history of the bases already described have gradually been accumulated, some of the products of their decomposition examined, and the pyrrol so frequently adverted to in the previous parts of this paper has been subjected to a full investigation. The details of these experiments form the subject of the present communication.

In the fourth part of these researches, I described a new base produced by the action of sodium upon picoline, to which I gave the name of Parapicoline, because it has the same composition as picoline, although the circumstances of its formation appeared to show that it had been produced by the combination of two molecules of that substance, so that its true formula would be C12H14N2. Unfortunately, its high boiling point, and tendency to decompose when distilled, made it impossible to determine its vapour density, which afforded the only means of ascertaining whether this hypothesis was correct; and it was only assumed, because similar cases of polymerisation had been established beyond a doubt in the case of other classes of organic compounds. In the hope of obtaining a similar base of lower boiling point, and therefore better adapted to the necessary experiments, I have submitted pyridine to the action of sodium, and the results of the inquiry are contained in the following pages.

The careful study of the products of destructive distillation has enriched organic chemistry with an extensive series of results of unexpected interest and importance. These results have affected, in no inconsiderable degree, the recent progress of the science; and their influence has been of a twofold character, both general and particular, exerted in the former case in the development of some of the more remarkable general doctrines of organic chemistry; in the latter, in the important light thrown by their investigation on the constitution of the substances from which they are derived, and the facilities they have afforded of following out connections, which the examination of the original substance either does not at all present to our view, or, at least, indicates only in an imperfect or dubious manner. Added to this, we have the remarkable fact of the appearance among these products of substances in some cases identical with those occurring in organised beings; and in others, presenting analogies of the very closest character with the actual products of vital affinity, which, taken together, afford abundant reason for pursuing the investigation of substances which have already afforded results of so remarkable a character.

An approach to the management of patients with large (greater than 4 cm) operable breast cancers is described. The conventional sequence of mastectomy followed by systemic therapy is reversed, allowing accurate measurements of response to individual forms of endocrine therapy or chemotherapy. Such a method not only permits individual selection of appropriate systemic therapy, but also allows clinical response to be related to histological and biochemical tumour parameters. A response was observed in eleven of twenty-three patients to endocrine treatment and in twelve of thirteen to combination chemotherapy. In five of the latter the response was histologically complete.

Fifteen patients with primary lymphoma of breast are reported from a 30-year review. Eight of the patients were diagnosed in the last 5 years of this review, suggesting either an increase in the incidence or an increasing awareness of this condition. The age range was from 17 to 77 years. All patients presented with a breast mass and nine had histologically proven axillary node involvement. One patient had Hodgkin's disease and the remainder were non-Hodgkin's lymphoma. Treatment was by a combination of surgery, radiotherapy and chemotherapy. During follow-up which varied from 4 to 20 years (median 8 years) three patients developed metachronous involvement of the opposite breast and three died from their disease. Prognosis was related to tumour histology and stage of disease. The three who died all had high grade centroblastic lymphoma, the three largest tumours and nodal involvement. Five and ten-year survivals were 85 per cent and 73 per cent respectively, better than the survival of patients for either other non-disseminated extranodal lymphomas or breast cancer.

Ocular lymphoma is an uncommon clinical entity with a propensity for intracranial extension. Palliation has been reported following radiotherapy, but the ultimate prognosis is poor, and significant treatment-related morbidity is common. Recent pharmacokinetic studies have suggested that sustained therapeutic drug concentrations are achievable in cerebrospinal fluid after systemic administration of high-dose cytosine arabinoside (Ara-C). These data led the authors to attempt treatment of a case of recurrent ocular lymphoma with high-dose Ara-C. Therapeutic drug levels were documented in intraocular fluids, and prolonged objective regression of tumor was seen. Systemic high-dose Ara-C deserves consideration for the treatment of ocular lymphoma.

On review of the histology of 1050 primary breast carcinomas, 103 cases of infiltrating lobular carcinoma were identified and clinical and survival data collected in each case. The tumours were then separated into four groups on the basis of histological pattern and these groups shown to have significantly different survival times. Assessment of the presence of in situ carcinoma, elastosis and intracytoplasmic lumina was performed in each case and the effect of these features on survival investigated. In addition to stage of disease at presentation, the major significant factor in predicting survival of patients with this type of invasive carcinoma is histological type.