Quantitation of metabolites in human blood serum by proton magnetic resonance spectroscopy. A comparative study of the use of formate and TSP as concentration standards.

Formate has been evaluated as an alternative standard to quantitate human serum metabolites in 1H NMR spin-echo spectra. The comparison between added formate and 3-(trimethylsilyl) 3,3,3,3-tetradeutero-propionic acid (TSP) shows that, unlike TSP, formate does not interact with serum macromolecules. Transverse and longitudinal proton relaxation times have been measured on several serum metabolites, in the presence of ammonium chloride. With the exception of glucose, values of metabolite concentrations derived from Hahn spin-echo spectra recorded on serum containing 15.4 mM exogenous formate as a standard, are in excellent agreement with the results of biochemical and chromatographic assays, after correction for differential relaxation effects. This approach can be readily used for quantitation of metabolites from blood serum (and eventually other physiological fluids) in normal and in pathological situations not involving disorders of endogenous formate metabolism.


Phosphorus metabolite characterization of human prostatic adenocarcinoma in a nude mouse model by 31P magnetic resonance spectroscopy and high pressure liquid chromatography.

A series of experiments were conducted to identify and quantify the phosphorus metabolites of DU 145 xenografts (a human prostatic adenocarcinoma cell line grown in nude mice) using 31P MRS and HPLC. The 31P spectral characteristics of DU 145 xenografts were compared to perfused DU 145 cells and to in situ human prostatic adenocarcinomas. These studies demonstrated that both DU 145 xenografts and perfused DU 145 cells exhibited reduced levels of phosphocreatine relative to spectra of in situ human prostatic adenocarcinomas. Elevated levels of phosphomonesters (PMEs) were observed in 31P spectra of both DU 145 xenografts and in situ human prostatic adenocarcinomas. The major components of the PME resonance of DU 145 xenografts were identified as phosphocholine and phosphoethanolamine. High levels of diphosphodiesters (DPDEs) were consistently observed for both DU 145 xenografts and perfused DU 145 cells, but were absent in 31P spectra in in situ primary human adenocarcinomas. In agreement with spectroscopic results, high pressure liquid chromatographic analyses of human tissue removed at surgery contained insignificant amounts of DPDEs while DU 145 xenografts had high levels of DPDEs consisting mainly of uridine-5'-diphospho-N-acetylgalactosamine (22.4 nmol/mg protein) and uridine-5'-diphospho-N-acetylglucosamine (7.4 nmol/mg protein).


Experimental characterization of the ISIS technique for volume selected NMR spectroscopy.

As clinical applications of MRS grow in number and complexity, there is a need for standardized methods for characterizing the performance of volume selection techniques. The results are presented of a thorough evaluation of a particular implementation of ISIS performed using a procedure which forms the basis of the method adopted by the European Community Concerted Action on MRS and MRI. We have found that ISIS localization is optimal when the volume of interest is slightly smaller than the region we wish to study. Contamination with extraneous signal has little T1 dependence so long as TR greater than T1 and the detection pulse angle is 90 degrees. However, a poorly optimized detection pulse results in T1-weighted contamination unless TR greater than 3T1. In the clinical context, this corresponds to a different degree of contamination for each peak in the spectrum. Adiabatic detection pulses were used in an attempt to overcome this problem without resorting to unacceptable TR values, but these were found to function less well than properly optimized rectangular pulses, even if the power was increased above the level determined by the system for B1 insensitivity. These detailed results pertain only to our system, but illustrate the importance of performing similar measurements as part of clinical spectroscopy programmes at other centres.


Direct absolute quantification of metabolites in the human brain with in vivo localized proton spectroscopy.

The absolute concentrations of the three major brain metabolites observable by in vivo proton spectroscopy--N-acetylaspartate(NAA), creatine and phosphocreatine (Cr and PCr) and choline (Cho)--have been measured at four standardized localizations in 34 healthy volunteers by in vivo localized proton spectroscopy using an external reference sample. The results show that the concentration of Cr and PCr as observed by in vivo MRS (5-6 mmol/L) is lower than that measured by other methods. The results are concordant with the hypothesis, that the Cr and PCr resonance as observed by proton spectroscopy is due mainly to PCr, whereas Cr remains invisible by being attached to a larger molecule. It is also demonstrated, that Cr and PCr is higher in the cerebellum than in the cerebrum, whereas NAA remains constant within the margin of error (8-9 mmol/L).


The biochemistry of living tissues: examination by MRS.

MRS defines the molecular state of water, the chemical environment of cells and tissues and the qualitative and quantitative state of intermediary metabolism. Because cancer has disordered physiology, obvious differences in MR spectra can be observed. However, the detailed understanding of the biochemistry of cancer will also emerge from careful, quantitative multinuclear MR. The intermediary metabolism of ATP, the Krebs cycle, creatine, cholines and lipids, is discussed. Finally, the biochemical challenge posed by oncogenes may be amenable to MR analyses.


Physiological properties of malignant tumours.

It is generally accepted that tumour microcirculation, blood flow, oxygen and nutrient supply, tissue pH distribution, and the bioenergetic status--factors which are usually closely linked and which define the so-called metabolic microenvironment--can markedly influence the therapeutic response of malignant tumours to conventional irradiation, chemotherapy, other non-surgical treatment modalities, and the cell proliferation activity within the tumours. Currently available information on the parameters defining the metabolic micromilieu in human tumours is presented in this paper. According to these data, significant variations in these relevant factors are likely to occur between different locations within a tumour, and between tumours of the same grading and clinical staging. Therefore, evaluation of the metabolic microenvironment in individual tumours before therapy and a corresponding 'fine-tuning' of treatment protocols for individual patients may result in an improved tumour response to treatment.


The choice of experimental models in cancer research: the key to ultimate success or failure?

The technologies available for assessing the size and physiological status of malignant tumours are becoming more and more sophisticated. Some of these detect phenotypic biochemical alterations resulting from the genetic changes associated with malignant transformation. Many, however, monitor the abnormal relationship between the tumour mass and the host, detecting pathophysiological changes which result from the host/tumour interaction. The most important of these involve the microregional heterogeneities of nutrients resulting from diffusion patterns around abnormal, newly-formed vascular networks, or inflammatory or immune responses of the host to the tumour. In order to validate new technologies for introduction to clinical medicine they are usually extensively tested in experimental models for cancer. The relevance of these models (whether in vitro cell cultures or experimental tumours) must be considered carefully at the outset, with the factors that influence the parameter being measured, e.g., oxygen or energy status, being given special attention. The genetic similarity of tumour and host, the site of tumour growth, the size of the tumour, the burden it imposes and the immunocompetence of the host are all important features of the experimental model. Inappropriate models may give totally misleading information which cannot be extrapolated to human cancers.


Practical applications of chemical shift imaging.

Methods of spectral localization are briefly reviewed and divided into two classes: those using phase encoding and those using frequency selective RF pulses in a constant gradient. A potentially troubling artifact in the latter case is the spatial misregistration of different compounds which causes serious errors in 31P spectra from smaller regions. Chemical shift imaging (CSI) is presented as a typical example of phase encoding techniques. An analytical expression for the relationship of the signal observed to the true signal (the point spread function) is derived. Examples of CSI in one, two, and three dimensions are used to illustrate the principles of this type of localization.


Phospholipid metabolites as indicators of cancer cell function.

NMR methods are being applied to study phospholipid metabolism of cancer cells by monitoring the resonances which appear in the 31P spectrum. This review, aside from considering the applicability of NMR to this specific pathway, raises the question of whether the phospholipid metabolite peaks observed by MR are indicators of cancer cell function or tumor response to treatment. After assessing the results from many investigations, it is concluded that there is no clear correlation and that a combination of techniques, including in vitro and extract studies, will be necessary for a more comprehensive evaluation of the in vivo data.


Practicalities of localization in animal and human tumours.

Factors affecting the selection and application of localization methods for measuring tumours by NMR spectroscopy are considered, with particular regard to the S/N ratio and to contaminating signal from outside the volume of interest. Methods of assessing the performance of localization techniques are considered, and their importance for quantitative measurements and comparative studies is discussed.


Bioluminescence and fluoroscopic imaging of tissue pH and metabolites in experimental brain tumors of cat.

The regional distribution of ATP, glucose, lactate and tissue pH was studied by bioluminescence and fluoroscopic imaging of intact cryostat sections of implantation tumors of cat. In tumors, marked heterogeneity of metabolites and pH was present: in solid parts ATP was similar to normal brain but glucose tended to decrease with an increase in lactate and pH to above normal; in necrobiotic regions ATP declined and pH became acidic. In peritumoral edema, ATP was consistently decreased whereas glucose, lactate and pH increased above normal. Correlation of ATP with water revealed an inverse relationship both in tumor and peritumoral edema but correlation of water with pH was direct in edema and inverse in tumors. The associations and dissociations of lactate, ATP and pH are interpreted in terms of aerobic and anaerobic glycolysis, as well as in respect to the extracellular localization of tumor edema. The findings are of relevance for the interpretation of volume selective NMR spectra and stress the importance of precise volume localization for differentiating between edema and tumor-mediated metabolic alterations.


Non-invasive MRS in new anticancer drug development.

In the rational development of anticancer drugs it is important to employ all the available pharmacological information. Early clinical trials provide an opportunity for hypothesis testing. MRS techniques have the potential to provide valuable data on the preclinical and clinical pharmacokinetics and pharmacodynamics of drugs non-invasively. Here we illustrate advantages and pitfalls of MRS using studies of two fluorine-containing cancer drugs: a beta,beta-difluoro analogue of the alkylating agent chlorambucil and a fluorinated derivative of the nitroimidazole misonidazole, Ro 07-0741. Limitations include signal quenching via protein binding and inadequate sensitivity for more potent drugs like beta,beta-difluorochlorambucil; but fluoromisonidazole was shown to accumulate in tumours and shows promise as a chemical probe for tumour hypoxia, detectable by 19F MRS.


Positron emission tomography for tumour assessment.

As positron emission tomography (PET) is outside of the main theme of this conference, it is necessary to outline what it offers as a method for assessing tissue function in vivo. This is followed by illustrations of how PET has and is being used to study the physiology and biochemistry of tumours and pharmacokinetics and pharmacology of anticancer agents. Strategies are offered as to how PET may be used for the development of new chemotherapeutic agents.


The use of the polymerase chain reaction in clinical oncology.

The polymerase chain reaction (PCR) is an extraordinary tool for studying cancer. It is both more sensitive and more rapid than any other detection method, and can be performed without special expertise. It is ideal for the detection of minimal residual disease, particularly in lymphoid malignancies, but also for any cancer with a genetic abnormality that is defined at the molecular level. Other uses, such as diagnosis of cancer based on detection of translocations or point mutations, have an intriguing potential, but remain investigational. At this point, few clinicians would be willing to base a diagnosis, let alone a treatment plan, on a diagnosis based on PCR findings without confirming histology.


The contribution made by cell death and oxygenation to 31P MRS observations of tumour energy metabolism.

This review discusses the relationship between tumour oxygenation status, tumour cell death and the 31P MRS parameters associated with cellular energy metabolism (phosphocreatine, nucleoside triphosphates and Pi). The presence of cells dying by apoptosis, and during mitosis would be unlikely to affect the 31P spectrum directly since they represent only a small fraction of tumour cells and remain energized until phagocytosed. Histologically necrotic cells also probably contribute nothing to the 31P spectrum. Instead, the spectrum appears to reflect the degree of hypoxia of the remaining viable cells, and the metabolic alterations required to sustain ATP synthesis as the oxygen supply diminishes. The biochemical theory developed to account for the 31P spectra of acutely hypoxic tissues does not apply to chronically hypoxic tumours. The concentrations of free ADP and Pi have major roles in the control of oxidative phosphorylation and glycolysis, as in normal tissues, but the precise relationships are still obscure. Cell-killing following therapy may indirectly affect 31P MRS parameters via changes in oxygen concentration brought about by an improvement in tumour blood flow and alterations in oxygen consumption rates and diffusion distances.


In vivo and ex vivo magnetic resonance spectroscopy as applied to pharmacokinetic studies with anticancer agents: a review.

The potential role of MRS in studying the pharmacokinetics of anticancer drugs is reviewed. In vivo and ex vivo MRS has been used extensively in studies with fluoropyrimidines. Results from preclinical models have demonstrated that biochemical modulation of 5-fluorouracil metabolism can be demonstrated by MRS. The more general potential of MRS is illustrated by studies with the antifolate CB3988 (C2-desamino-C2-methyl-N10-propargyl-2'-trifluoromethyl-5,8-dideazafolic acid). Studies in mice and rats have shown that hepatobiliary clearance and renal elimination can be measured non-invasively by MRS. Comparison of half-lives derived from MRS and high performance liquid chromatography data gave reasonable agreement. In addition, MRI was used to localize drug-derived material within the abdominal cavity. The application of ex vivo MRS is illustrated by studies on the urinary excretion of platinum complexes. 1H-MRS has been used to demonstrate the presence of the cyclobutanedicarboxylate leaving group, both free and platinum bound, in the urine of patients treated with carboplatin. With iproplatin 195Pt NMR has been used to demonstrate in vivo reduction of this Pt(IV) complex to Pt(II) complexes. Finally, the application of MRS to the study of the molecular pharmacology of alkylating agents (a nitrogen mustard and N-methyl-N-nitrosourea) is discussed.


Measurement of tumor blood flow by deuterium NMR and the effects of modifiers.

Tumor metabolism is directly coupled to tumor blood flow (TBF) and both metabolism and blood flow may be determinants of tumor response to treatment. Since NMR has been used extensively to monitor tumor metabolism noninvasively, development of NMR-based methods for TBF measurement was motivated by the desire to examine the roles tumor metabolism and blood flow may play as determinants of therapeutic response. The concept of using deuterated water as an NMR-detectable, flow-limited tracer for the measurement of tissue blood flow (or capillary perfusion) was introduced in 1987 by Ackerman and coworkers (Proc. Natl., Acad. Sci., USA 84, 4099-4102 (1987)). Since that time, methods have been devised using both spectroscopic and imaging detection for TBF measurement based on either clearance or uptake of deuterated water. In general, the clearance methods are more straightforward to implement, while the uptake methods are less invasive to the tumor. When used with appropriate caution, both approaches yield reliable results. To date, these methods have been applied in a relatively limited number of animal tumors. However, their use is increasing and some of these methods ultimately should be applicable in human tumors.


Clinical experimentation in magnetic resonance spectroscopy: a perspective from the National Cancer Institute.

This paper describes the National Cancer Institute activities in clinical MRS, including a recent international conference organized by the Diagnostic Imaging Research Branch, a research agenda developed by the conference faculty members of one of the research programs proposed by the author.


Acute renal failure in cancer patients.

Compromise of kidney function in patients with serious medical illnesses, including cancer, is a serious and potentially fatal complication. In cancer patients, the types of renal injury that may occur are more varied than in patients with other underlying illnesses, and definition of the etiology of the decline in renal function may have important therapeutic and prognostic implications. This review article discusses the clinical manifestations and the diagnostic workup of insults to the kidney in patients with cancer. Therapy (excluding dialysis) for each type of renal insufficiency is briefly reviewed.


Recognizing the oral manifestations of AIDS.

The first sign of HIV infection may be an unusual or rapidly progressive condition of the oral cavity, including malignancies such as Kaposi's sarcoma. Early diagnosis of these oral conditions can lead to early diagnosis of HIV infection and subsequent treatment with antiretroviral agents that may improve the prognosis. This illustrated review outlines the presenting signs and symptoms of the most common oral manifestations of the AIDS virus, including hairy leukoplakia, candidiasis, Kaposi's sarcoma, periodontal disease, salivary gland disease, necrotizing stomatitis, and infection with herpes and human papillomavirus.


Genetic etiology of lung cancer.

Although the clinical management of lung cancer has not changed substantially over the past decade, this same time period has witnessed exciting new developments concerning the origins of this disease. These findings support the hypothesis that lung cancer, as well as other common adult tumors, arise as a result of somatic mutations to a specific group of cellular genes referred to as oncogenes and tumor suppressor genes. New strategies for the prevention and treatment of lung cancer will emerge as we identify the mechanisms that control mutation rates for these target genes and gain a better understanding of the role these genes play in coordinating normal cell growth and differentiation.


Expanded programme on immunization (EPI). Safety of high titre measles vaccines.

Unexpected results suggesting decreased survival when compared with standard titre vaccine administered at 9 months of age have been found in some field studies evaluating the performance of high titre measles vaccine. Analytical difficulties have arisen because the studies were not specifically designed to measure survival. Nonetheless, careful analysis of the results from all of the high titre vaccine trials showed decreased survival of high titre vaccine recipients, in areas with high background mortality rates, compared with recipients of standard measles vaccines at 9 months. No systematic biases could be found in the studies to explain these differences. Statistical analysis of these data suggested that the findings were unlikely to be attributable to chance alone. The panel recommended that high titre measles vaccine derived from the original Edmonston measles vaccine isolate should no longer be recommended for use in immunization programmes. Further post-licensure field studies of new measles vaccines should take into account the results of these studies. Additional detailed epidemiological studies in populations that have received high titre vaccines and their controls were encouraged.


Accident & emergency: care and transfer of the burns patient.

A patient with major burns requires intervention from highly skilled nursing and medical teams on arrival at the accident and emergency department, and those staff without proper training can lack confidence in dealing with such a situation. The author offers guidance and advice for nurses in A&E on initial treatment of the burns patient, and discusses the preparation necessary before transferring the victim to another area, as well as the transfer itself.


Should nurses wear name badges?

In the third and final part of the series of articles on the implications of the 'named nurse' initiative, Stephen Wright looks at the issue of name badges and whether wearing them enhances nurse/patient relationships or poses personal risks to staff. Much of the current information related to the debate is anecdotal, suggesting that formal research on the issues would be useful.


Learning disabilities. Using hydrotherapy: maximising benefits.

People with a learning disability are increasingly using hydrotherapy for exercise, socialising, and the release of tension and energy. For those with a physical disability, it offers an opportunity for independent activity from which they may be precluded outside the hydrotherapy pool. The author discusses guidelines for staff involved in hydrotherapy sessions before examining in detail the benefits this form of treatment has to offer.


Development of an in vitro bladder model.

The first of the three articles in this series (1) expounded the case for a broader approach to research design in nursing. In particular, the experimental approach and the use of laboratory studies were highlighted as areas that nurses have tended to neglect. This second article explores the development of an in vitro bladder model for use in experiments examining infections in catheterised patients.


Pressure sores and intra-operative risk.

The enormous cost of pressure sore care is well documented (1, 2), but a review of the available literature shows few studies on the genesis of intra-operative pressure sores exist and the contribution of operating room exposure as an aetiological factor is largely undefined. This article provides a brief overview of the aetiology of pressure sores, details interface pressures reported on operating tables, and critically reviews the literature suggesting a link between events during the intra-operative period and post-operative pressure sore formation.


The bladder model: clinical implications.

The first two articles in this series (1, 2) discussed the importance of the experimental approach within nursing research, and described the development of a bladder model which could be used to investigate errors in practice. The final article will document the use of this model in examining the design features of four urinary drainage bags and in investigating the effect of a potential error in practice.


The epidemiology of acquired immunodeficiency syndrome and associated tumours in Europe.

By the end of September 1991, more than 60,000 cases of acquired immunodeficiency syndrome (AIDS) had been reported to the World Health Organization (WHO) by 31 countries in the WHO European region. Most of the cases (58,280/60,485-96%) were recorded in western Europe, chiefly in five countries: France (16,552 cases), Italy (10,584), Spain (10,101), Germany (6,968) and the United Kingdom (5,065). From the first reports in 1981 of European cases of AIDS until 1987, AIDS spread faster in the northern and central areas than elsewhere in the European region. Since then, the spread of the epidemic has been remarkably more rapid in southern Europe, while in eastern Europe AIDS is still in an early phase. More than 70% of the cases among homosexual or bisexual men were from the northern part of Europe, while the cases among intravenous drug users (IVDUs) were concentrated in the southern European countries, principally Italy and Spain. Over time, an increasing proportion of cases was recorded among IVDUs and in heterosexuals. More than 10,000 patients in Europe were diagnosed as having Kaposi's sarcoma (KS) (14% of all AIDS cases) or non-Hodgkin's lymphoma (NHL) (3%) as the presenting clinical manifestation of AIDS. The possibility of predicting the evolution of the epidemic in Europe depends heavily on the development of unbiased monitoring systems for HIV infection in the general population (i.e. anonymous unlinked testing).


Response after withdrawal of tamoxifen and progestogens in advanced breast cancer.

Tumor response after withdrawal of endocrine therapy for advanced breast cancer with estrogens and androgens is well described. There have been few reports of withdrawal responses (WRs) after cessation of treatment with the newer antiestrogens and progestogens. We assessed WR in women after cessation of adjuvant therapy at first relapse, and after progression on first, second or third line endocrine therapy for advanced disease. One of seven patients (14%) responded after cessation of tamoxifen adjuvant therapy at relapse. Sixty-five of 72 patients were evaluable for WR after cessation of tamoxifen as first line therapy for advanced disease. There were five partial responses (8%) and 14 (22%) 'no change' with a median duration of WR of 10 months (range 3-40 months). WR were seen mainly in soft tissue disease but there were two responses in lung and two in bone. Four of 21 (19%) patients had a WR after cessation of norethisterone acetate (3) and tamoxifen (1), all used as second line therapy. WR are therefore demonstrable after cessation of tamoxifen and norethisterone acetate with durations of response similar to those found with additive therapy. Assessment of WR may represent a way of prolonging the overall response duration in patients with relatively indolent metastatic breast cancer, particularly in soft tissues.


Plicamycin and pamidronate in symptomatic tumor-related hypercalcemia: a prospective randomized crossover trial.

We have conducted a randomized crossover comparative trial of a single-dose course of disodium (3-amino-1-hydroxypropylidene) bisphosphonate pentahydrate (pamidronate) and plicamycin in 48 patients with a first occurrence of tumor-related hypercalcemia. All patients had hypercalcaemia-associated symptoms and serum-calcium levels (corrected for total protein) greater than or equal to 2.80 mmol/l. Pamidronate and plicamycin were given concurrently with rehydration immediately after diagnosis of hypercalcaemia was made. Both agents lowered serum calcium levels significantly within 1 week, with 88% of the evaluable patients in the pamidronate group and 45% of those in the plicamycin group achieving normocalcemia (p less than 0.01). In the patients who received pamidronate, the duration of normocalcemia was longer (p less than 0.05) and there was a significant decrease in serum creatinine (p less than 0.05). Vomiting occurred in 8 of 22 evaluable patients (36%) who received plicamycin, but in none of 25 evaluable patients who received pamidronate (P less than 0.01). Phlebitis occurred at the infusion site in more of the pamidronate-treated patients (P less than 0.05). Hypocalcemia, which occurred in 8 of 25 evaluable patients (32%) in the pamidronate group and in 1 of 22 of those (5%) in the plicamycin group, was either clinically asymptomatic or mild, except in one pamidronate-treated patient. Overall, pamidronate was found to be more effective and better tolerated than plicamycin, thereby confirming results of previous studies that showed pamidronate to be an effective, simple, and safe agent for the relief of the morbidity associated with tumor-related hypercalcemia.


The role of age at menarche and at menopause on breast cancer risk: combined evidence from four case-control studies.

The role of age at menarche and at menopause on breast cancer risk was reassessed in a combined analysis of four Italian case-control studies including a total of 6,075 cases and 5,492 controls. The risk of breast cancer was lower in women whose menarche occurred at age 15 or over, but there was no evidence for the risk to increase with decreasing age at menarche below age 15. Compared with women with earlier menarche, the relative risk (RR) was 0.9 (95% confidence interval, CI 0.7-1.0) for those with menarche at age 15, 0.8 (95% CI 0.6-0.9) for menarche at 16, and 0.7 (95% CI 0.5-0.8) for menarche at age 17 or over. There was no significant interaction between age at menarche and study centre or age at diagnosis, parity and age at first birth. In relation to age at menopause, compared with women whose menopause occurred at age 40 or less, the relative risk was 1.1 (95% CI 0.8-1.3) between 40 and 44, 1.2 (95% CI 0.9-1.4) between 45 and 49, 1.4 (95% CI 1.2-1.8) between 50 and 53, and 1.4 (95% CI 1.1-1.8) above 53. The risk estimates were comparable in various studies, and the trend in risk with age at menopause was statistically significant. The risk estimates tended to be somewhat higher at peri-menopausal age (45 to 54 years), but no consistent pattern was evident across subsequent strata of age, and the interaction with age was not significant. Likewise, no consistent interaction was observed with parity, age at first birth or body mass index.(ABSTRACT TRUNCATED AT 250 WORDS)


Subsets of tumors responsive to cisplatin or carboplatin combinations in patients with carcinoma of unknown primary site. A Hellenic Cooperative Oncology Group Study.

In this retrospective analysis 48 patients with metastatic undifferentiated carcinoma, adenocarcinoma and epidermoid carcinoma of unknown origin were studied. The purpose of this analysis was to evaluate both the response rate and the toxicity of combination chemotherapy containing cisplatin or carboplatin, and to attempt to identify certain clinical subsets of patients sensitive to these drugs. Four patients were not evaluable and 13 (29.5%), eight of the 34 treated with regimens containing cisplatin and 5/14 with carboplatin-based chemotherapy, responded to treatment. Six of the 23 with undifferentiated tumours, 4/17 with adenocarcinomas and 3/8 with epidermoid cancers responded to chemotherapy. Four of 6 women with adenocarcinoma of the peritoneal cavity, 5/11 with undifferentiated carcinomas with midline distribution and 3/5 with epidermoid carcinomas of the cervical nodes responded. Seven patients achieved complete and six partial remissions. The mean duration of response was nine months; a number of patients enjoyed prolonged and/or durable remissions. Toxicity was tolerable. We conclude that: (a) both cisplatin and carboplatin are active agents in this syndrome with one-third of the evaluable patients responding, and (b) there may be chemosensitive subgroups, such as patients with peritoneal adenocarcinomatosis, undifferentiated carcinoma with midline distribution and metastatic epidermoid carcinoma of the neck nodes. The effectiveness of carboplatin in these patients and the responsiveness of metastatic epidermoid carcinoma of unknown origin have not been adequately dealt with in the literature.


Treatment with alpha-interferon versus alpha-interferon in combination with streptozocin and doxorubicin in patients with malignant carcinoid tumors: a randomized trial.

An open randomized trial was performed to compare the effect of recombinant interferon-alpha 2a (rIFN-alpha 2a) (group A, n = 12) versus rIFN-alpha 2a in combination with chemotherapy (group B, n = 11) in patients with malignant carcinoid tumors. Both groups received rIFN-alpha 2a at a dose of 3 MU/m2 s.c. three times weekly during the first 6 months. IFN was discontinued every third week in group B, followed by an i.v. injection of 2 g streptozocin and 40 mg/m2 doxorubicin. After 6 months group A showed one complete biochemical response (CR), 9 patients with stable disease (SD) and 2 who progressed (PD). Two patients had a partial reduction (PR) of tumor size, 9 showed SD and one PD. All patients in group B demonstrated SD. Chemotherapy was withdrawn after 6 months and all patients continued with rIFN-alpha 2a at an increased dose of 3 MU/m2 five days/week for a further 6 months. After 12 months 6 patients showed PR, 12 SD and one PD biochemically. Tumor size showed SD in 18 patients and PD in one. One patient died from cardiomyopathy, probably induced by doxorubicin. Antibodies against rIFN-alpha 2a developed in 41% of the patients. In conclusion, we detected no difference in response rates between the two treatment groups. Adverse reactions from the combination were considerable. The frequent development of IFN antibodies might have interfered with the therapeutic results.


Pharmacokinetics and metabolism of epirubicin administered as i.v. bolus and 48-h infusion in patients with advanced soft-tissue sarcoma.

We have studied the pharmacokinetics of epirubicin after its administration in sarcoma patients either as an i.v. bolus or as a 48-h infusion (5 courses each; 9 patients in total). Bolus injection was followed by a three exponential decay in plasma, with half-lives of 2.43 min, 1.95 h and 21.7 h; 48-h infusions were characterized by the very rapid establishment of a plasma plateau concentration followed by a biexponential decay after stopping the infusion. Pharmacokinetic parameters such as total plasma clearance, total volume of distribution, mean residence time and elimination half-life were similar, irrespective of the duration of the administration. In contrast, the relative amounts of the metabolites of epirubicin were reduced when the drug was administered over 48 h; in particular, the plasma levels of epirubicin glucuronide never exceeded those of epirubicin, which always occur after bolus injection. This may result from a lower availability of epirubicin for metabolism. These results now require validation in a larger group of patients using a cross-over design.


Bi-weekly 2-day schedule of high-dose folinic acid, 5-fluorouracil bolus and infusion in pretreated advanced epithelial ovarian cancer: a phase II study.

Twenty patients with documented progression after two or three cisplatin-based regimens for advanced epithelial ovarian carcinoma were treated with high-dose folinic acid (200 mg/m2), 5-fluorouracil bolus (400 mg/m2) and continuous infusion (600 mg/m2) for two consecutive days every two weeks. One clinically complete and two partial responses were observed in 16 evaluable patients, with 5 remaining stable. Median survival was 9 months. Toxicity was mild. This combination achieved a 19% (95% confidence interval 4%-46%) response rate in heavily pretreated cisplatin-resistant patients.


Multicenter phase II trial of brequinar sodium in patients with advanced melanoma.

Seventeen patients with advanced melanoma and no prior exposure to chemotherapy were treated with brequinar sodium as first-line chemotherapy. Brequinar was given at a median weekly dose of 1200 mg/m2 intravenously. In 14 patients evaluable for efficacy, there were no objective responses. The toxicity was moderate. We conclude that, at this dose and schedule, brequinar has no activity in advanced melanoma.


Meta-analysis: the fashion of summing-up evidence. Part II: Interpretations and uses.

In this commentary, we use evidence produced by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) ten-year update of a meta-analysis of trials of adjuvant therapies for early breast cancer which started prior to 1985 to illustrate aspects of interpretations and uses of meta-analysis results. The following issues are discussed: i) The meta-analysis provides an average summary for the effect of a treatment. Greater statistical power is obtained by increasing the number of events contributing to the analysis. However, summing up the results of various trials necessitates the loss of individual information concerning the magnitude of treatment effects which depend on tumor- and patient-related factors. Subgroup analyses within the meta-analysis process allow some recovery of such features; ii) The absolute benefit obtained from an effective treatment depends not only on the relative benefit of the treatment but also on the prognosis of the individual patients; iii) The results are more immediately applicable if less reliance is placed on the arithmetic construct inherent in the overview, using instead unconfounded information about the value of treatments actually administered. This avoids the need to extrapolate the effect for one component of the therapy by assuming a lack of interaction with its other components; iv) Although indirect comparisons between different meta-analyses are regularly made to pick the "winner" from among tested treatment modalities, it is unlikely that the optimal therapeutic regimen can be defined via such indirect comparisons, though such comparisons may raise interesting, testable hypotheses.


A proposal for a simple staging system for intermediate grade lymphoma and immunoblastic lymphoma based on the 'tumor score'.

A new staging system for intermediate grade lymphomas and immunoblastic lymphomas is described. This system is based on the tumor score which consists of assigning a point to each one of five variables that have been previously shown to have a high prognostic value. Ann Arbor stages III-IV, presence of bulky mass, elevation of B-2 microglobulin and LDH as well as presence of 'B' symptoms are the variables utilized in this system. When we applied this tumor score system to a population of 144 patients uniformly treated with CHOP/Bleo/CMED protocol, we observed that this system can accurately divide the population into two prognostic groups without an intermediate category. The first group is made up of those patients with a score of 0-2 points while the second group consists of patients with a score of > or = 3 points. The first group has a time-to-treatment failure (TTF) of 83% at three years in contrast to the second group whose TTF was 24%. If we compare this system with other commonly used systems in our institution, such as Ann Arbor, M.D. Anderson clinical staging system, and M.D. Anderson serological staging system, we observed that the tumor score system is not only more specific and sensitive than the others but also was capable of eliminating an intermediate risk group, thus facilitating therapeutic choices. This tumor score system is easy to apply and potentially reproducible in any institution.


Severe vascular adverse effects with thrombocytopenia and renal failure following emetogenic chemotherapy and ondansetron.

During late 1991, a series of severe adverse events involving thrombocytopenia, renal insufficiency and thrombotic episodes was observed in patients receiving emetogenic chemotherapy. Two patients died, one of renal failure and one of cerebral haemorrhage in the presence of thrombocytopenia. Other severe side effects included thrombosis of the aorta causing paraplegia and multifocal cerebral infarctions. Common exposure features included the use of ondansetron and dexamethasone as antiemetics, and in most of the cases high dose (100 mg/M2 or more) cisplatin. Retrospective review of a series of patients treated with similar cytotoxic regimens for similar diseases before the use of ondansetron revealed no similar adverse effects, but no substantial differences were observed in renal function or haematologic toxicity in the two groups overall. Sporadic adverse vascular events have been observed before the use of ondansetron. The mechanism remains unknown, and it is not clear whether ondansetron was a factor in the unusual incidence of such events in the present series.


Sequential estrogen receptor determinations from primary breast cancer and at relapse: prognostic and therapeutic relevance. The International Breast Cancer Study Group (formerly Ludwig Group).

We retrospectively evaluated 401 selected patients who had estrogen receptor (ER) assays both at primary surgery and at relapse in an accessible site to determine the clinical relevance of the subsequent ER determination. The median time between ER assessments was 27 months (range: 2-122 months). The median follow-up time from diagnosis was 6 years (range: 2-12 years). For patients with ER+ tumors at primary diagnosis, 29% (76/261) had ER- tumors at relapse, while for ER- primaries, the conversion rate was 33% (46/140). Conversions from ER+ to ER- occurred more often when the time interval between assays was less than one year (p = 0.004), while conversions from ER- to ER+ tended to occur late (beyond three years; p = 0.0003). Treatments received between assays (usually adjuvant therapy) had only a slight influence on ER status conversion. Post-relapse survival was poor for patients who had the biopsy accessible recurrence within one year; an expression of the aggressive nature of the disease. Among patients whose accessible relapse was beyond one year, those with ER- primaries who converted to ER+ had a longer survival than those whose recurrence was classified again as ER- (p = 0.006). This group of patients with ER- primaries who recurred beyond one year with an ER+ tumor in an accessible site represented 29% (40/140) of all patients with ER- primaries and had an estimated overall survival rate of more than 60% at 6 years from the accessible relapse. ER determination upon relapse within one year has very little clinical relevance.(ABSTRACT TRUNCATED AT 250 WORDS)


Recombinant tumor necrosis factor for superficial bladder tumors.

Twenty patients with histologically documented superficial bladder cancer (Ta, T1, Tis) were treated with intravesical administration of TNF 400-1800 micrograms. Of 18 patients with a marker lesion, 2 obtained a complete response for 8+ and 18 months. Two had a partial response and were given other intravesical therapies after 5 and 7 months. No or minimal systemic absorption of TNF was observed and documented in 4 of 20 patients by pharmacokinetic studies, and no patients developed antibodies to intravesically administered TNF. TNF was well tolerated in doses up to 1800 micrograms. No systemic or local side effects were observed. Modest activity was attained with intravesical TNF, even in pretreated patients.


The Stanford experience with combined procarbazine, Alkeran and vinblastine (PAVe) and radiotherapy for locally extensive and advanced stage Hodgkin's disease.

This report describes the efficacy and toxicity of PAVe (procarbazine, Alkeran, vinblastine) and irradiation (RT) in the management of 159 patients with locally extensive or advanced stage Hodgkin's disease (HD) at Stanford University. Patients received six courses of chemotherapy alternating with RT. The extent of RT and the schedule of treatment varied according to the stage of disease. About 2/3 of patients received PAVe/RT in the setting of prospective, randomized clinical trials. The rate of complete response was 93%. With a median follow-up of seven years (range 2-17), the 15 year actuarial freedom from progression (FFP) is 78% and overall survival is 75%. Ten-year FFP by stage is: 80% for locally extensive stage II, 90% for stage IIIA and 70% for stage IIIB. Excellent and equal results were attained with PAVe/RT vs. MOP(P) (mustard, Oncovin, procarbazine with or without prednisone)/RT in the randomized combined modality studies. Progression or recurrence was documented in 30 patients and was more common in irradiated sites. PAVe was well tolerated acutely. There were no treatment related fatalities. Twenty-three (14%) patients were admitted to the hospital for neutropenic fever. Five second malignancies have occurred after PAVe/RT only: one myelodysplastic syndrome, one acute myelogenous leukemia, one non-Hodgkin's lymphoma and two solid tumors including a case of non-small cell lung cancer and an in situ carcinoma of the cervix. Three patients died from myocardial infarction several years after the completion of treatment. These mature data show that PAVe/RT is effective and well-tolerated therapy for locally extensive stage II and IIIA/B HD.(ABSTRACT TRUNCATED AT 250 WORDS)


Preclinical antitumour activity and animal toxicology studies of rhizoxin, a novel tubulin-interacting agent.

Rhizoxin is a 16-membered antifungal macrocyclic lactone isolated from the plant pathogenic fungus Rhizopus chinensis. The compound binds to tubulin, preventing microtubule formation, and inhibiting mitosis. It possesses antitumour activity in vivo against various preclinical murine models, both leukaemias and solid tumours model, as well as in vincristine- and doxorubicin-resistant leukaemia lines. In the present study, cytotoxic activity was observed in human tumour cell lines in vitro at very low concentrations (+/- 10(-10) M) particularly against melanoma, colon, renal, non-small cell and small cell lung cancer. In vivo antitumour activity was demonstrated in murine P388 and L1210 murine leukaemias, solid tumour models B16 melanoma and M5076 sarcoma, and in 5 out of 9 human solid tumour xenografts: LOX melanoma, MX-1 breast cancer, non-small cell lung cancer A549, and small cell lung cancers LXFS 605 and LXFS 650. The absence of cross-resistance to vinca alkaloids was confirmed in vivo against the vincristine-resistant P388 leukaemia subline and the vincristine-resistant human small cell lung cancer LXFS 650. In addition, the antitumour activity of rhizoxin was improved by prolonged or repeated drug administration indicating a schedule dependency. In animal toxicology studies, transient changes in erythrocyte and leukocyte numbers, local phlebitis, diarrhea, and spermatogenic arrest were observed. The LD10 value of rhizoxin after a single intravenous injection was 2.8 mg/kg (8.4 mg/m2). One-tenth of the mouse equivalent LD10 (0.84 mg/m2), the starting dose for clinical phase I studies, was considered to be safe in rats.(ABSTRACT TRUNCATED AT 250 WORDS)


Treatment of primary refractory or relapsed acute lymphoblastic leukemia (ALL) in children.

Thirty-one intensively pretreated children with ALL in first bone marrow relapse or refractory to initial therapy were treated with a combination of intermediate-dose Ara-C and idarubicin (IDA). Twenty-four patients (77%) achieved complete remission (CR), 8 patients relapsed early and 2 were removed from the study. Fourteen (45% of the original 31 patients) underwent bone marrow transplant (BMT) and 7 of them (22%) are still in continuous CR (CCR) with a median follow-up of 18 months. These results confirm that it is possible to achieve CR even in ALL children who failed on an initial intensive regimen. Newer modalities of post-remission therapy, especially for children lacking an HLA donor, should be considered.


Thyroid, pulmonary, and cardiac sequelae after treatment for Hodgkin's disease.

Modern therapy of Hodgkin's disease has produced the expectation of long-term survival for most patients. However, in the process of achieving the current success, a price has been paid in unwanted, delayed side effects. Apart from second malignancies and gonadal impairment, other adverse consequences can be identified. This paper will briefly summarize recent findings related to thyroid, pulmonary and cardiac dysfunction. Attention to treatment regimens and careful follow-up may help to prevent or manage these complications, which are uncommonly life-threatening. The desire to refine the treatment of Hodgkin's disease must not result in a reduction of the overall chance of cure.


Second cancer after the treatment for Hodgkin's disease: a report from the International Database on Hodgkin's Disease.

Twenty institutions/cooperative groups tabulated second cancers among 12,411 patients diagnosed with Hodgkin's disease between 1960 and 1987, giving 82,850 person-years of observation. Overall, 631 second cancers were observed, as compared with 223.25 expected (observed (O) to expected (E) ratio 2.83, p < 0.001) at least one year after the diagnosis of Hodgkin's disease. Second cancers were acute leukaemias (AL) in 158 cases as compared with 5.75 expected (O/E = 27.48, p < 0.001), non-Hodgkin's lymphomas (NHL) in 106 cases as compared with 3.34 expected (O/E = 31.77, p < 0.001), and solid tumors (ST) in 367 cases as compared with 214.16 expected (O/E = 1.71, p < 0.001), with no differences between males and females. Excess of ST was observed for the following anatomic sites: salivary gland, small intestine, colon, bronchus, pleura, bone, skin other than melanoma and thyroid in males; salivary gland, bronchus, pleura, skin other than melanoma and breast in females. While the excess of second AL and NHL was significant over the 1-14 year period after the start of initial therapy, that of second ST became apparent after the fifth year, increasing with time. Overall, the 15-year cumulative incidence rate of second cancer was 11.2%. It was 2.2%, 1.8% and 7.5% for second AL, NHL and ST, respectively. While the cumulative incidence of AL and NHL plateaued after 17 years, that of ST was still increasing. To analyse whether a particular treatment category was associated with an increased risk of second cancer, a prognostic study was performed on the 11,241 patients who achieved a complete remission and were continuously disease-free. Overall, 87 patients developed an AL, 68 a NHL, and 231 a ST. Combined modality treatments including MOPP or MOPP-like chemotherapy were associated with the higher risk of second AL (Relative risk (RR) = 17.11; p < 0.001) followed by age above 50 (RR > 4.50; p < 0.001), advanced clinical stage (RR > 2.50; p < 0.001), splenectomy (RR = 1.65; p < 0.05) and MOPP or MOPP-like chemotherapy used alone (RR = 2.20; p < 0.05). Factors associated with an increased risk of second NHL were age above 30 (RR > 3.5; p < 0.001), male gender (RR = 1.82; p < 0.05) and clinical stage III (RR = 1.70; p < 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)


Activation of cytokines in Hodgkin's disease.

The complex histological pattern in Hodgkin's disease and in part in large cell anaplastic lymphomas (ALCL) suggests that close interactions exist between the tumor cells and reactive bystander cells. These interactions are most likely mediated by short ranged cytokines. The production of cytokines was analyzed in primary tissues and cell lines from Hodgkin's disease and ALCL by enzyme linked immunosorbent tests (ELISA), Northern blotting, immunohistological staining and in situ hybridization experiments. Our results indicate that Hodgkin's disease derived cell lines produce a variety of cytokines, such as IL1 alpha, IL4, IL5, IL6, IL8, IL9, TNF alpha and TNF beta but not IL1 beta, IL2, IL3 and G-CSF. In addition, the receptors for IL6 were detected in some of the cell lines. The expression of IL6 and IL6 receptors and IL9 has been confirmed for some primary tissues of Hodgkin's disease. From our data, we conclude that IL6, IL9 and additional cytokines are involved in the biology of Hodgkin's disease and ALCL.


Cell adhesion molecules in Hodgkin's disease.

The fact that Hodgkin's cells are capable of binding lymphocytes has been observed both in vivo and in vitro. It is not unexpected, therefore, that cultured Hodgkin's cells have been found to express a high number of adhesive sites, including representative molecules from various adhesion molecule families.


Preliminary report: growth of Hodgkin's lymphoma derived cells in immune compromised mice.

Until now there has been no satisfactory animal host for the in vivo growth of Hodgkin lymphoma cells. With the exception of one mutant subline (L540Cy) none of the other Hodgkin derived cell lines nor Hodgkin's disease (HD) derived lymphatic tissue could be propagated in suitable animal systems such as the T-cell deficient nude mouse. Recently, the severe combined immunodeficient (SCID-) mouse has been demonstrated as a possible recipient for human lymphatic tissue. In the present study, we have evaluated the SCID mouse as a possible in vivo model for Hodgkin's lymphoma. I) We demonstrate that seven permanent cell lines derived from patients with Hodgkin's disease grow progressively in SCID mice after subcutaneous and intraperitoneal inoculation. II) In addition, after intravenous injection, two of these lines (L540, L540Cy) show a disseminated growth pattern resembling the distribution of HD cells in man (involvement of lymph nodes, liver and bone marrow but not of spleen). The observed reproducible disseminated tumor growth establishes the SCID mouse as a new animal model for experimental treatment strategies in Hodgkin's lymphoma. III) We present preliminary results of the transplantation of primary material from 13 patients with Hodgkin's disease. Material from two patients induced human tumors in the SCID mice recipients, whereas material from two others led to the induction of mouse lymphomas. The human tumors showed three distinct histological patterns: 1) Lymphoproliferative disease (LPD); 2) anaplastic large cell lymphomas (ALCL); 3) Hodgkin like lesions (HLL). In vitro cell lines established from human SCID mouse tumors were of B-lymphoid origin, were EBV-positive and showed numerical and some structural chromosomal aberrations of varying degree.


Histopathological classification of Hodgkin's lymphomas. Results from the reference pathology of the German Hodgkin Trial.

Diagnostic biopsies of 1,140 previously untreated patients with Hodgkin's lymphoma from the German Hodgkin Therapy Trial were evaluated by a panel of 4 histopathologists. Each case was classified by consensus of the four according to an extended Rye-System including the diversifying of NS.HD and the unclassifiable cases. The interobserver agreement rate was 92.1% among the panel members regarding the final classification. Primary Hodgkin diagnosis was approved in 91.7% (1045/1140 cases). The distribution of the 1,140 cases within this system was (in %) as follows: 2.7 LP.HD, 57.9 NS.HD, 17.3 MC.HD, 0.7 LD.HD, 13 HD of unclassifiable subtypes, 6.3 of not certain HD, 1.9 Non-Hodgkin Lymphoma, 1 case of non malignancy. Grading of NS.HD into 2 subgroups according to the British classification differed conspicuously by 84.5% versus 15.5% and 71.6% versus 28.4% in British results. This divergency is explained by interobserver disagreement ranking from 43% to 85%.


Controversies in the use of diagnostic staging laparotomy and splenectomy in the management of Hodgkin's disease.

Considerable controversy exists over the routine use of diagnostic staging laparotomy and splenectomy in the workup of patients with Hodgkin's disease. With the development of effective, and perhaps less toxic chemotherapy the need for staging laparotomy has somewhat decreased. In the United States it is still common to recommend surgical staging for early stage patients when the results influence the choice of treatment. Since 20%-30% of clinically staged (CS) IA-IIA and 35% of CS IB-IIB patients with Hodgkin's disease will have occult splenic or upper abdominal nodal involvement not detected by LAG, CT, MRI, or gallium imaging, staging laparotomy allows for selection of patients either to receive limited radiation therapy alone (most PS I-II patients) or chemotherapy with or without radiation (PS III). In Europe, Canada, and South America most patients are clinically staged without a laparotomy. Patients are selected for treatment with radiation therapy alone or for chemotherapy with or without radiation on the basis of clinical prognostic factors. This article details the current arguments for and against the use of staging laparotomy.


Diagnostic imaging studies in patients with newly diagnosed Hodgkin's disease.

A variety of diagnostic imaging studies are used to evaluate patients with newly diagnosed Hodgkin's disease which provide important information to determine stage and guide patient management. The following will review the current status of diagnostic imaging studies as applied to evaluation of the thorax, abdomen and pelvis, with comment on areas under investigation.


International Database on Hodgkin's Disease: a cooperative effort to determine treatment outcome.

In an effort to better determine the outcome of patients treated for Hodgkin's disease, twenty institutions/cooperative groups in the western world agreed in 1988 to participate in the development of a large data base by sending data to be analyzed by a common statistical design. Data was obtained from both patients randomized on prospective trials and patients treated by standard protocol but not randomized. Overall statistics on 14,315 adult patients treated from the early 1960s to 1987 were collected. This data was first presented at the Paris International Workshop and Symposium held on June 28-30, 1989. The proceedings, published in 1990, include a detailed description of the data, and prognostic studies on laparotomy findings, response to initial therapy, relapse-free survival, overall survival, and secondary malignancies. The International Database on Hodgkin's Disease represents a compromise between two more classical approaches such as the use of randomized trials and metaanalyses. It should serve as a model for the study of other types of cancer. It has been successful because of interest, time, and the cooperation of physicians in academic centers from much of the western world.


Hodgkin's disease in 92 patients with HIV infection: the Italian experience. GICAT (Italian Cooperative Group on AIDS & Tumors).

Ninety-two cases of Hodgkin's disease (HD) in patients with HIV infection have been collected by the Italian Cooperative Group on AIDS and Tumors (G.I.C.A.T.). In accordance with the epidemiology of HIV infection in Italy, 82% were intravenous drug users (IVDU), 8% homosexual men, 5% IVDU+homosexuals and 5% heterosexuals. At diagnosis of HD, 16% had AIDS, 20% AIDS related complex (ARC), 33% persistent generalized lymphadenopathy (PGL) and 31% were asymptomatic. Fifty-three percent of the patients had stage IV disease and 70% mixed cellularity and lymphocytic depletion. Forty-six patients were treated with MOPP or MOPP [symbol: see text] ABVD +/- radiotherapy (zidovudine was not given) with complete remission (CR) in 54% and partial remission (PR) in 46% of the patients. Fifty-six percent of these patients developed opportunistic infections (OI) during therapy or follow-up. Sixteen patients were treated with epirubicin, bleomycin and vinblastine (EBV) and concomitant zidovudine, with CR in 44% and PR in 38%. However, only one of these patients developed OI during therapy or follow-up. The clinico-pathological features and natural history of HD in HIV setting are peculiar and quite distinct from those observed in HD in the general population. Better combined chemotherapy and antiretroviral therapy is needed in order to ameliorate the CR rate and decrease the OI in patients with HIV infection and HD.


Treatment of children with Hodgkin's disease--results of the German Pediatric Oncology Group.

Six hundred sixty-seven children under age 16 were enrolled in 4 consecutive studies in West Germany between 1978 and 1990. These trials were mainly designed to reduce the long-term sequelae of high dose extended-field irradiation as well as the late effects of chemotherapy, in the context of combined modality treatment for all stages. Treatment concepts and results of studies HD-82, HD-85 and HD-87 are presented here. Patients with stages IA/B and IIA were treated with 2 cycles of OPPA (HD-82, n = 100) or OPA without procarbazine (HD-85, n = 53; HD-87, n = 104), followed by involved field irradiation (IFI) using 35 Gy (HD-82, HD-85) or 30 Gy (HD-87). Kaplan-Meier estimates (KME) for event-free survival (survival) at 4.5 years are 99% (100%) in HD-82, 85% (98%) in HD-85 and 88% (100%) in HD-87. Thus, 2 x OPPA is a highly effective chemotherapy eradicating occult microfoci in the non-irradiated adjacent fields, whereas 2 x OPA is less efficacious. Reduction of the radiation dose to 30 Gy (IFI) within the combined modality concept does not affect treatment outcome. About 30% of the boys treated with 2 x OPPA, but none of the girls and none of the boys treated without procarbazine (PC) showed elevated FSH-levels indicating gonadal dysfunction. No secondary leukemias and preleukemias were observed.(ABSTRACT TRUNCATED AT 250 WORDS)


Radiotherapy versus combined modality in early stages.

In early stage Hodgkin's disease the optimal choice of treatment for the individual patient is still an unresolved issue. So far, twenty-two randomized trials of radiotherapy alone versus radiotherapy plus combination chemotherapy have been carried out worldwide. The preliminary results of a global metaanalysis of these trials indicate that we still do not definitively know whether or not the addition of prophylactic chemotherapy up front improves survival. Arguments in favour of the addition of chemotherapy up front are: that laparotomy may be avoided, that radiation fields and doses may perhaps be reduced, and that the stress of experiencing a relapse is avoided in many patients. The major argument against the use of chemotherapy up front is: that by careful staging and selection of patients and by careful radiotherapy techniques the number of patients exposed to potentially toxic chemotherapy may be kept at a minimum. Recently, trials have been carried out testing chemotherapy alone. The results of these trials are however conflicting. In order not to jeopardize the good results achieved with the standard treatments developed over the last three decades, newer treatment approaches should be carefully tested in large randomized trials before being implemented for general clinical use.


NOVP and radiotherapy for early-staged Hodgkin's disease: an interim analysis.

Modern treatment plans for early staged Hodgkin's disease must focus on optimal disease-free survival results without laparotomy, minimal acute toxicity, and reduced long-term complications. We have treated 69 adult patients with stage I-II Hodgkin's disease, 40 of whom had bulky disease, B symptoms, or hilar disease, and 22 with stage III disease with 3 cycles of NOVP (Novantrone, vincristine, vinblastine, prednisone) and radiotherapy. Only patients with stage III1 disease involving the celiac axis without para-aortic or pelvic involvement, had to undergo laparotomy prior to treatment. Three patients did not respond to NOVP: two of these did not respond to MOPP or ABDIC, and two are currently without relapse following bone marrow transplant. With a median follow-up of 18 months, 62 with stage I-II and 19 with stage III remain without relapse, and 91 patients are alive. Tolerance to therapy was excellent with minimal nausea, myalgias, and alopecia. We conclude that this regimen for Hodgkin's disease provides good results for clinically staged I-III disease, but longer follow-up may demonstrate prognostic factors which will influence our results.


Conceptual problems in relation to dose escalation in the first remission of Hodgkin's disease.

Autologous bone marrow transplantation (ABMT) is now widely used as salvage therapy in Hodgkin's disease but its value will have to be finally proved by the use of randomised trials. However ABMT is now being used in first remission. The justification of this is based on the view that patients can be identified once remission is achieved who are at high risk of relapse and that these patients will be prevented from relapsing by high dose therapy and ABMT in first remission with an 'acceptable' procedure related toxicity. The choice of patients judged to be suitably poor risk is critical but unproven. The only report of ABMT in CR1 yet published [1] is encouraging but can be criticised on a number of grounds. The incidence of procedure related mortality is a significant factor in determining the balance of any risk/benefit analysis. Randomised trials need to be undertaken but must identify the correct group of patients to avoid treating with high dose therapy those who may already have been cured by initial therapy.


Autologous bone marrow transplantation for Hodgkin's disease.

Autologous bone marrow and/or peripheral blood stem cell transplantation is being performed increasingly frequently as a treatment for Hodgkin's disease. While patients with refractory disease can sometimes be cured, the results are better in patients who are still chemotherapy sensitive. The use of high dose therapy as part of the primary treatment for high risk patients is now being studied.


Digitalis and heart failure: does digitalis really produce beneficial effects through a positive inotropic action?

Although digitalis was introduced to medicine long ago, the drug is still extensively used in clinical practice today. Opinions on its mechanism of action have undergone much change in the course of time, and the way in which cardiovascular effects are produced is still not completely clear. Limitations and contraindications for the use of digitalis substances are reported, especially in the treatment of ischemic heart disease. Preliminary data regarding the effects of digitalis on the diastolic phase are unfavorable, although the relationship between digitalis and diastolic function ought to be studied in greater depth in various clinical conditions. In spite of many recent trials, the old question of the usefulness of digitalis in the chronic treatment of patients in sinus rhythm and heart failure is still debated. An important clinical benefit in the chronic use of digitalis appears restricted to a relatively small proportion of patients with severe congestive heart failure, while in the majority of chronically treated subjects the effects of the drug are scanty or insignificant. The beneficial effect of digitalis used chronically is essentially believed to be due to its positive inotropic action. Since the vagomimetic and the antiadrenergic effects of digitalis have been demonstrated to be independent from its inotropic action, they could be considered determinants of the clinical benefits of digitalis. These indirect effects may be useful in the control of the negative neuroendocrine response developing during congestive heart failure. Thus the statement that digitalis is essentially an inotropic agent seems restrictive; its definition should reflect the favorable effects obtained in some cases of congestive heart failure rather than its various and contrasting underlying mechanisms of action.


A comparison of the effects of captopril and flosequinan in patients with severe heart failure.

Angiotensin converting enzyme inhibitors have greatly improved the treatment of patients with chronic heart failure but they are not effective in all patients, and their use may be limited by side effects. There is, therefore, a need to investigate new drugs and to compare their efficacy with angiotensin converting enzyme inhibitors. Flosequinan is a new direct-acting vasodilator that has been shown to be effective in placebo-controlled studies. Patients with chronic heart failure in NYHA classes II or III who remained symptomatic despite at least 80 mg of frusemide daily were recruited from two centers. Following a single-blind placebo run-in period, the patients were randomized double blind to either the addition of captopril or flosequinan for 6 weeks. Following a further 2-week placebo washout period, they were then given the alternative treatment. Symptom-limited treadmill exercise times, scores of perceived exertion, and corridor walk tests were measured at two weekly intervals during the study. Twenty-five patients entered the study, 16 of whom completed without a change in diuretic dose. Five patients were withdrawn while taking captopril and two while taking flosequinan; two were withdrawn during the placebo washout period. For those patients who completed the study, flosequinan increased treadmill exercise tolerance from a mean (SEM) placebo time of 11.5 (1.0) minutes by 2.4 (0.6) (p = 0.0002) and captopril from 12.0 (0.8) minutes by 1.2 (0.6) minutes (p = 0.08). Comparison of the other measures of efficacy revealed no difference between the groups. In this short-term study flosequinan appeared to be equal in efficacy to captopril.


A multicenter comparison of nicorandil and diltiazem on serum lipid, apolipoprotein, and lipoprotein levels in patients with ischemic heart disease.

The effects of nicorandil and diltiazem on serum lipid, apolipoprotein, and lipoprotein levels in 37 patients with ischemic heart disease were examined in a randomized, multicenter study. Nicorandil (n = 20, 10-40 mg/day, b.i.d.) and diltiazem (n = 17, 60-240 mg/day, b.i.d.) were administered for 12 weeks. Both nicorandil and diltiazem administration showed an effective antianginal effect. Diltiazem administration showed a significant hypotensive action. There were no significant changes in serum lipids, apolipoproteins, and lipoproteins for both nicorandil and diltiazem. There were no significant changes in body weight, uric acid, and fasting blood sugar levels during the test period for both drugs. These data show that nicorandil, like diltiazem, does not have any adverse effects on lipid metabolism and that it is a favorable drug to use as an agent for treating arteriosclerotic heart disease.


Intravenous atenolol in elderly patients in the early phase of acute myocardial infarction.

The aim of this study was to assess the hemodynamic response to intravenous atenolol in elderly patients with acute myocardial infarction. We studied 14 elderly men, aged 64-85 years, and 14 younger men, aged 29-48 years, in the early postfibrinolytic phase of acute myocardial infarction. All the patients were in Killip class I. A triple-lumen Swan-Ganz thermodilution catheter was introduced into the right heart chambers. The patients received 5 mg intravenous atenolol over 5 minutes. All hemodynamic parameters were measured before and 10 minutes after atenolol. The hemodynamic characteristics and the location and extent of acute myocardial infarction were the same in both groups before atenolol. The hemodynamic changes after atenolol administration were the same in the two groups, but the stroke volume and cardiac indexes decreased to a greater extent in the elderly (p = .01 and p = .0001, respectively). These results indicate that intravenous atenolol in the early postfibrinolytic phase of acute myocardial infarction is safe in Killip class I elderly patients, although the cardiac and stroke volume indexes decrease, and the increase in the total systemic resistance is more in older than in younger patients.


Antianginal effects of amlodipine at a single dose on exertional angina patients using treadmill exercise testing--a randomized crossover study in comparison with placebo.

With eight cases of stable exertional angina as subjects, the antianginal action and sustained effects of single 10 mg oral doses of new calcium antagonists amlodipine were assessed by treadmill exercise tests in randomized crossover trials with respect to a placebo. Exercise tests were conducted before as well as 4, 8, and 24 hours after administration, and plasma amlodipine concentration was investigated at the same times. The maximal exercise time was 299 +/- 43 seconds before as compared with 346 +/- 49 seconds 4 hours after administration and 368 +/- 50 seconds 8 hours after administration, a significant prolongation in each case (p < 0.01). Moreover, the exercise time elapsed until 1 mm of ST-segment depression, as well as the ST-segment depression measured at the same time, were both significantly improved as compared with the placebo results. The plasma amlodipine concentration reached a peak 8 hours after administration and displayed an effective level even 24 hours after administration. The value of delta PRP measured at the same time during the exercise test was also significantly reduced as compared with the placebo results, even 24 hours after administration of amlodipine. These findings supported the conclusion that single 10-mg doses of amlodipine provide stable antianginal action over a 24-hour period.


Comparison of effects of enalapril and captopril on serum potassium concentration in the treatment of malignant hypertension.

To compare the effects of enalapril and captopril on blood pressure, serum creatinine (S-Cr), and potassium (S-K) levels, patients with malignant hypertension treated with either 5-10 mg of enalapril (eight cases) or 75-400 mg of captopril (eight cases) were investigated retrospectively. After 2 weeks of treatment, the average blood pressure fell from 214/138 to 132/89 mmHg on enalapril and from 240/145 to 147/95 mmHg on captopril. The percent change in mean blood pressure during the 2 weeks of treatment with enalapril (-35.6 +/- 4.0 SE%) was similar to that with captopril (-35.8 +/- 2.8%). S-Cr did not change in both groups, while S-K increased significantly from 3.9 +/- 0.2 to 5.2 +/- 0.2 mEq/l on enalapril and from 3.6 +/- 0.2 to 4.2 +/- 0.1 mEq/l on captopril. S-K at the second week was significantly higher in the enalapril than in the captopril group. The maximum S-Cr concentration during the treatment was correlated with the corresponding S-K concentration similarly in both groups. These results indicate that both enalapril and captopril increase S-K without deterioration of renal function in patients with malignant hypertension and that the way these drugs are used in clinical practice may be more likely to result in elevated S-K with enalapril.


Inhibition of platelet accumulation by beta 1-adrenoceptor blockade in the thoracic aorta of rabbits subjected to experimental sympathetic activation.

Arterial platelet adhesion is an initiating event in the thrombo-embolic complications of atherosclerosis and may also accelerate the development rate of atherosclerotic lesions. Psychosocial stress has been shown to accelerate atherogenesis in animals, an effect probably mediated via beta-adrenoceptor activation. In view of the postulated roles of platelets and beta-adrenoceptor activation in atherosclerosis development, we decided to test whether beta blockade affects arterial platelet accumulation. We studied the accumulation of radioactivity from 111In-labelled platelets on the wall of the thoracic aorta of rabbits as a measure of platelet accumulation. During the exposure to the labelled platelets, the animals were also exposed to 3 hours of chloralose anesthesia. This is a reproducible model of experimental sympathetic activation, including beta-adrenoceptor activation, which we used to amplify possible effects of beta-blockade on platelet-vessel wall interaction. The effectiveness of the anesthesia in increasing sympathetic activity was verified by significant rises in mean arterial blood pressure (from 77 to 88 mmHg), heart rate (190 to 290 bpm), and plasma levels of norepinephrine (1.0 to 3.3 nM) and epinephrine (0.13 to 0.83 nM). In chloralose anesthetized rabbits, approximately 30 x 10(-9)% of the injected 111In accumulated in each square millimeter of intima at unbranched thoracic aorta. Platelet accumulation was significantly higher at arterial branching points, 70% higher at intercostal artery bifurcations, and 150% higher at coronary artery bifurcations than in unbranched aortic intima. Pretreatment with metoprolol in a dose resulting in "therapeutic" plasma levels significantly reduced platelet accumulation by 48% in unbranched aorta, 65% at intercostal, and 53% at coronary artery bifurcations.(ABSTRACT TRUNCATED AT 250 WORDS)


Comparative class 1 electrophysiologic and anticholinergic effects of disopyramide and its main metabolite (mono-N-dealkylated disopyramide) in healthy humans.

During steady-state treatment with disopyramide, its main and active metabolite, mono-N-dealkylated disopyramide, was reported to reach concentrations that were equal to or higher than the parent drug in 25% of 70 evaluated patients. This metabolite has been found to have a more pronounced anticholinergic action than the parent drug on in vitro evaluation, but neither its anticholinergic nor its direct electrophysiologic effects on the human heart have been properly assessed. We therefore compared the acute electrophysiologic and anticholinergic effects (the standard being atropine, 0.04 mg/kg) of disopyramide and its main metabolite, given 2 mg/kg body weight intravenously to 10 healthy individuals in a double-blind, randomized, crossover design. The anticholinergic effect of these substances on sinus and atrioventricular node function was unexpectedly found to be of similar magnitude and more pronounced than previously thought (at least one-third the effects of the atropine dose). The class 1 electrophysiologic effects were as follows: intra-atrial and His-Purkinje conduction (the PA and the HV interval, respectively) was prolonged 33% (95% CI: 18-47%) and 27% (21-32%) by disopyramide, and 15% (10-19%) and 13% (10-17%), respectively, by the metabolite. Disopyramide also prolonged the QRS, JT, and QT intervals by 15% (9-21%), 10% (8-13%), and 10% (7-12%), respectively. The metabolite caused a 9% (7-12%) prolongation of the QRS interval (significantly less than disopyramide), but shortened repolarization (as reflected by the JT interval) by -7% (-2 to -11%; p < 0.01), which is similar to the acute effects of lidocaine 2 mg/kg body weight.(ABSTRACT TRUNCATED AT 250 WORDS)


Half-squaring in responses of cat striate cells.

Simple cells in striate cortex have been depicted as rectified linear operators, and complex cells have been depicted as energy mechanisms (constructed from the squared sums of linear operator outputs). This paper discusses two essential hypotheses of the linear/energy model: (1) that a cell's selectivity is due to an underlying (spatiotemporal and binocular) linear stage; and (2) that a cell's firing rate depends on the squared output of the underlying linear stage. This paper reviews physiological measurements of cat striate cell responses, and concludes that both of these hypotheses are supported by the data.


Electrophysiological sensitivity of carotenoid deficient and replaced Drosophila.

R1-6 dominated electroretinographic (ERG) spectral sensitivities were determined as a function of days posteclosion from carotenoid deprived and replaced white-eyed Drosophila. The sensitivity of flies deprived from egg to adult waxed (about 1.5 log units by day 3), and then waned gradually from 3-11 days (over 2 log units by day 11). Carotenoid replacement (feeding nothing but carrot juice) effected recovery to near the replete controls' level in about 1 day throughout (tested at 0, 4, and 11 days). The normal yellow cornmeal-agar-molasses-brewers yeast fly food (in our laboratory, supplemented with beta-carotene) renders a slower recovery (requiring 7-9 days) since it is a medium designed largely for larval growth. Placing replete adults on deprivational medium did not create a deprivational syndrome in over 11 days. At 3-7 days, deprived flies reared and maintained in constant darkness had substantially enhanced sensitivity, beyond the 1.5 log unit increment already described for cyclic light rearing conditions. All spectral analyses are consistent with the ultraviolet (UV) sensitization of the blue (480 nm) rhodopsin by a replacement-dependent retinoid including two unexpected findings: (1) sensitivity recovery with carrot juice was so fast that the UV peak was already high at 6 h; and (2) the waxing of the deprived fly's sensitivity in dark rearing was so great that the UV peak was present at 4-7 days.


Monocular enucleation reduces immunoreactivity to the calcium-binding protein calbindin 28 kD in the rhesus monkey lateral geniculate nucleus.

The calcium-binding proteins calbindin (CaBP) and parvalbumin (PV) are important in regulating intracellular calcium in brain cells. PV immunoreactivity is reduced by enucleation in the lateral geniculate nucleus (LGN) and by enucleation and visual deprivation in the striate cortex of adult monkeys. The effects of enucleation and visual deprivation on CaBP immunoreactivity in the LGN are not known. We therefore have studied cells and neuropil in the LGN that are labeled by antibodies to CaBP in normal and visually deprived Rhesus monkeys to determine if there is an effect on this calcium-binding protein. One group of monkeys had one eye removed 2 weeks to 4.3 years before sacrifice. A second group had one eye occluded with opaque lenses from infancy without enucleation. A final group had one eye occluded long-term followed by short-term enucleation 2 weeks before sacrifice. In normal monkeys, CaBP-immunoreactive neurons were found throughout the LGN. They were sparsely distributed within the six main laminae, and more densely distributed within layer S and the interlaminar zones (ILZ). The labeled ILZ neurons had a distinct morphology, with fusiform somata and elaborate dendritic trees that were confined primarily to the ILZ. Most CaBP-labeled neurons in the main layers had dendrites that radiated in all directions from the soma. ILZ and main layer cells labeled by CaBP thus probably represent two different cell types. Monocular enucleation with or without occlusion produced a significant reduction in antibody labeling in the deafferented laminae. Field measures revealed an average 11.5% reduction in optical density in each deafferented lamina compared to its adjacent, nondeprived layer. The differences in field optical density between deprived and nondeprived layers were statistically significant. CaBP neurons were still visible, but the optical density of antibody labeling in these cells also was reduced. Occlusion without enucleation had no effect. Thus, deafferentation, but not light deprivation, reduces concentrations of CaBP in monkey LGN. This effect is different than that seen in striate cortex of adult monkeys, where visual deprivation as well as enucleation alters CaBP immunoreactivity.


A circadian clock in the Limulus brain transmits synchronous efferent signals to all eyes.

A circadian clock in the brain of the horseshoe crab, Limulus polyphemus, has an important role in the function of the peripheral visual system. At night, the clock transmits neural activity to the lateral, ventral, and median eyes via efferent optic nerve fibers. The activity occurs in synchronous bursts (maximum rate of 2 bursts/s) with individual efferent fibers contributing a single spike in each burst. The circadian efferent activity originates in the protocerebrum. Lateral connections synchronize the efferent activity recorded from the two halves of the protocerebrum, suggesting the existence of bilateral circadian oscillators. Circadian efferent activity survives excision of the brain and isolation of the protocerebrum. We conclude that circadian clock and its complex neural circuitry are fundamental components of the Limulus visual system.


Direction selectivity of cells in the cat's striate cortex: differences between bar and grating stimuli.

We have investigated the notion that directional responses of cells in the visual cortex depend on the type of stimulus used to drive the cell. Specifically, we have asked if sinusoidal gratings provide a different estimate of direction selectivity than bars that are brighter or darker than the background. Using standard techniques, we recorded from 176 cells in the visual cortex of nine cats. For each cell, bright bars, dark bars, and sinusoidal gratings were presented in a randomly interleaved fashion. Complex cells exhibited around twice as many direction-selective as nondirection-selective responses. Estimates of direction selectivity were nearly identical for bright and dark bars and for gratings. For simple cells, a similar ratio of direction-selective to nondirection-selective responses was observed for gratings. However, a larger proportion of simple cells were classified as direction selective when bars were used for stimulation. A simple cell that exhibited direction selectivity to a grating behaved in a similar manner when stimulated with bright or dark bars. However, in contrast to complex cells, some simple cells classed as directionally nonselective on the basis of their responses to gratings, displayed directionally selective behavior to bars. In addition, the preferred directions for dark and bright bars sometimes differed. These results demonstrate that the classification of a simple cell as directionally selective or nonselective can depend critically on the visual stimulus used.


The effect of contrast on the visual response of lagged and nonlagged cells in the cat lateral geniculate nucleus.

The response vs. contrast characteristics of different cell classes in the dorsal lateral geniculate nucleus (LGN) were compared. The luminance of a stationary flashing light spot was varied stepwise while the background luminance was constant. Lagged X cells had lower slope of the response vs. contrast curve (contrast gain), and they reached the midpoint of the response range over which the cells' response varied (dynamic response range) at higher contrast than nonlagged X cells. These results indicated that nonlagged cells are well suited for detection of small contrasts, whereas lagged cells may discriminate between contrasts over a larger range. The contrast gain and the contrast corresponding to the midpoint of the dynamic response range were similar for X and Y cells. The latency to onset and to half-rise of the visual response decreased with increasing contrast, most pronounced for lagged cells. Even at the highest contrasts, the latency of lagged cells remained longer than for nonlagged cells. For many lagged cells, the latency to half-fall decreased with increasing contrast. It is shown that the differences in the response vs. contrast characteristics between lagged and nonlagged X cells in the cat are similar to the differences between the parvocellular and magnocellular neurones in the monkey.


Steady discharges of X and Y retinal ganglion cells of cat under photopic illuminance.

The discharges of ON- and OFF-center X and Y retinal ganglion cells in the presence of stationary patterns or of a uniform field of photopic luminance were recorded from urethane-anesthetized adult cats. The interval statistics and power spectra of these discharges were determined from these discharge records. The patterned stimuli were selected and positioned with respect to a cell's receptive field so as to generate steady discharges that were different in mean discharge rate from that cell's discharge for the diffuse field. The interval statistics of discharges recorded for diffuse or patterned illumination for all cell types can be modeled, approximately, as coming from renewal processes with gamma-distributed intervals. The gamma order of the interval distributions was found to be nearly proportional to the mean discharge rate for X cells, but not for Y cells. Typical values for the gamma orders and their dependence on mean rate for different cell types are given. The same model of a renewal process with gamma-distributed intervals is used to model the measured power spectra and performs well. When the gamma order is proportional to mean rate, the power spectral density at low temporal frequencies is independent of discharge rate. Gamma order was proportional to mean rate for X cells but not for Y cells. Nonetheless, the power spectral densities of both cell types at low frequencies were approximately independent of discharge rate. Hence, noise in this band of frequencies can be considered additive. The consequences of departures from the renewal process and of the gamma order not being proportional to mean rate are considered. The significance of different rates of discharge for signaling is discussed.


The relative time course of axonal loss from the optic nerve of the developing guinea pig is consistent with that of other mammals.

The relative timing of a number of events during the development of the visual system has recently been suggested to be consistent across a number of mammalian species (Dreher & Robinson, 1988). Some conflicting reports, however, had suggested that the precocial guinea pig might represent an exception to the generalized scheme. A quantitative study was thus carried out on the development of the optic nerve and retina of the guinea pig. Consistent with the prediction of a stable relative time course of mammalian visual development, axons and growth cones were found in the optic stalk from the 24th postconceptional day (40% of the period from conception to eye opening--the cecal period), the peak number of axons was observed on the 32nd postconceptional day (56% of the cecal period), and the phase of rapid axonal loss extended to the 39th and 42nd postconceptional days (68-74% of the cecal period). The number of axons in the adult optic nerve (117,000) represented about 37% of the peak number of axons. Additional observations indicated that during development of the optic nerve the mean axonal diameter increased approximately threefold from 0.31 microns to 1.06 microns. As in other mammals studied so far, myelination was first noted after the period of rapid axonal loss and continued until in the adult 97% of axons were found to be myelinated. In the retina, the presence of pyknotic profiles in the ganglion cell layers extends throughout the periods of loss of the optic nerve axons. Finally, the presence of pyknotic profiles in the amacrine sublayer suggest that in the guinea pig, as in other mammalian species, there is a loss of displaced amacrine cells as well as ganglion cells from the ganglion cell layer.


Motion defined exclusively by second-order characteristics does not evoke optokinetic nystagmus.

We showed high-contrast, second-order motion stimuli to subjects whilst recording their horizontal eye movements. These stimuli were very poor at evoking optokinetic nystagmus. Smooth-pursuit eye movements and fixation were reduced by a masking band +/- 2.5 deg above and below an imaginary fixation point. First-order stimuli evoked vigorous optokinetic nystagmus (OKN) under identical conditions and also when matched for apparent contrast. These findings are discussed in terms of the site of detection of second-order motion.


The Limulus-eye view of the world.

The compound lateral eye of the adult horseshoe crab, Limulus polyphemus, views the world with approximately 1000 ommatidia. Their optical properties and orientation determine the eye's resolution, field of view, and light collecting ability. Optic axes of adjacent ommatidia diverge from 1-15 deg with an average value of 5.5 deg yielding an average resolution of 0.1 cycles/deg. Resolution is not uniform across the eye: along horizontal planes, it is maximal in the anterior region of the eye (0.22 cycle/deg) and minimal in the posterior region (0.07 cycle/deg); along vertical planes, it is maximal near or just below the horizon (0.23 cycle/deg) and minimal above the horizon (0.04 cycle/deg). Together the ommatidia of one eye view approximately 60% of the hemispheric world on one side of the body. There is little binocular overlap (< 1% of total field). Ommatidial facets of up to 320 microns in diameter (among the largest known in the animal kingdom) make the eye a superb light collector. Limulus are known to use vision to find mates both day and night. Apparently, the optics of the lateral eye sample a large enough part of the world with sufficient resolution and light-collecting ability for the animal to succeed at this essential task.


Visual responsiveness and direction selectivity of cells in area 18 during local reversible inactivation of area 17 in cats.

We have investigated the effects of inactivation of localized sites in area 17 on the visual responses of cells in visuotopically corresponding regions of area 18. Experiments were performed on adult normal cats. The striate cortex was inactivated by the injection of nanoliters of lidocaine hydrochloride or of gamma-aminobutyric acid (GABA) dissolved in a staining solution. Responses of the simple and complex cells of area 18 to optimally oriented light and dark bars moving in the two directions of motion were recorded before, during, and after the drug injection. Two main effects are described. First, for a substantial number of cells, the drug injection provoked an overall reduction of the cell's visual responses. This nonspecific effect largely predominated in the complex cell family (76% of the units affected). This effect is consistent with the presence of long-range excitatory connections in the visual cortex. Second, the inactivation of area 17 could affect specific receptive-field properties of cells in area 18. The main specific effect was a loss of direction selectivity of a number of cells in area 18, mainly in the simple family (more than 53% of the units affected). The change in direction selectivity comes either from a disinhibitory effect in the nonpreferred direction or from a reduction of response in the preferred direction. It is proposed that the disinhibitory effects were mediated by inhibitory interneurones within area 18. In a very few cases, the change of directional preference was associated with a modification of the cell's response profile. These results showed that the signals from area 17 are necessary to drive a number of units in area 18, and that area 17 can contribute to, or at least modulate, the receptive-field properties of a large number of cells in the parastriate area.


ATP-independent deactivation of squid rhodopsin.

Deactivation of light-activated squid rhodopsin was studied in vitro using GTP gamma S binding by G-protein as a direct measure of rhodopsin activity. Deactivation was inhibited by dilution of the retinal suspension or by removal of soluble components. Deactivation could be restored by addition of soluble material to washed membranes. These results indicate that the deactivation is not due entirely to a conformational transition within rhodopsin itself, but depends on the interaction with other molecules. The possibility that phosphorylation is involved in the deactivation was studied. Deactivation occurred in the presence and absence of added ATP. Deactivation also occurred in the presence of kinase inhibitors and after addition of apyrase, which reduced residual ATP levels to below 1 microM. These results indicate that light-induced phosphorylation is not required for deactivation of squid rhodopsin. In this regard deactivation of squid rhodopsin is different from that of vertebrate rhodopsin, which requires phosphorylation.


Morphogenesis of retinal ganglion cells during formation of the fovea in the Rhesus macaque.

The morphology of retinal ganglion cells within the central retina during formation of the fovea was examined in retinal explants with horseradish-peroxidase histochemistry. A foveal depression was first apparent in retinal wholemounts at embryonic day 112 (E112; gestational term is approximately 165 days). At earlier fetal ages, the site of the future fovea was identified by several criteria that included peak density of ganglion cells, lack of blood vessels in the inner retinal layers, arcuate fiber bundles, and the absence of rod outer segments in the photoreceptor layer. Prior to E112, the terminal dendritic arbor of retinal ganglion cells within the central retina extended into the inner plexiform layer and were located directly beneath their somas of origin or at most were slightly displaced from it. For example, at E90 the mean horizontal displacement of the geometric center of the dendritic arbor from the somas of cells within 600 microns of the estimated center of the future fovea was 4.1 microns (S.D. 2.7, range 1.0-10.0, n = 97). Following formation of the foveal depression the dendritic arbors of cells were significantly displaced from their somas. For example, at E138 the mean displacement was 41.2 microns (S.D. 12.2, range 12.0-56.0, n = 97). The displacement of the dendritic arbor which occurred during this period was not accounted for by areal growth of the dendritic arbor, the somas, or the retina, but was produced by the lengthening of the primary dendritic trunk. Moreover, no significant displacement was observed within the remaining 1.5-6.5 mm of the central retina. These observations provide evidence supporting early speculations that the formation of the foveal pit occurs, in part, by the radial migration of ganglion cells from the center of the fovea during its formation. Our analyses suggest that this migration occurs by the lengthening of the primary dendrite presumably by the addition of membrane. This migration is in a direction opposite to the inward movement of photoreceptors that occurs during late fetal and early postnatal periods (Packer et al., 1990, Journal of Comparative Neurology 298, 472-493).


Spectral sensitivity of monocularly deprived cats.

The reports of rod-dominated psychophysical spectral sensitivity from the deprived eye of monocularly lid-sutured (MD) monkeys are intriguing but difficult to reconcile with the absence of any reported deprivation effects in retina. As most studies of MD retina have been from cat, we have examined psychophysically the increment threshold spectral sensitivity of MD cats using both reaction time and simultaneous two-choice behavioral procedures. Although the deprived eyes exhibited an absolute increment threshold sensitivity deficit, both rod and cone spectral sensitivity functions were obtained on large white backgrounds. This normal transition from rod to cone vision, as background luminance increased, was also found in threshold vs. intensity functions. Using their deprived eye, some cats exhibited a rod spectral sensitivity function when a smaller, normally photopic, background was used providing some support for a hypothesis that the rod-dominated spectral sensitivity observed in monkey may represent detection of scattered stimulus light. Alternatively monocular deprivation may reveal a rod-dominated mechanism which exists in monkey but not in cat.