Studies on the nature of antihemophilic factor (factor VIII). Further evidence relating the AHF-like antigens in normal and hemophilic plasmas.

Normal human antihemophilic factor (AHF, factor VIII) and the protein antigenically related to it in hemophilic plasma both appeared in the void volume of columns of agarose (Sepharose 4B) during purification of these agents. On ultracentrifugation upon sucrose gradients, both agents had sedimentation characteristics similar to those of an S30 marker. After reduction, the polypeptide chains of purified normal AHF and of the nonfunctional agent from hemophilic patients had an apparent molecular weight of 200,000 as determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis. These observations suggest that AHF, purified as described, exists as a large molecule with subunits of molecular weight of approximately 200,000. Antisera to normal AHF and the nonfunctional agent from hemophilic plasma appeared to be directed against antigens of similar electrophoretic mobility and precipitating characteristics, present in normal and hemophilic plasma but deficient in severe von Willebrand's disease plasma. Both antisera neutralized the AHF clot-promoting activity present in normal plasma, and this property was removed by absorption of the antisera with concentrates of normal or hemophilic plasma but to a greatly reduced extent by concentrates of von Willebrand's disease plasma. These findings suggest that the antigen detected in normal plasma by the antisera appears on a molecule participating in the AHF clot-promoting reaction.

Effect of mopidamol on survival in carcinoma of the lung and colon: final report of Veterans Administration Cooperative Study No. 188.

Mopidamol (RA-233), a derivative of dipyridamole, is a phosphodiesterase inhibitor that has been shown previously to limit progression of malignancy in certain experimental animal models and in a pilot study in humans. RA-233 plus chemotherapy was compared with chemotherapy alone in a 5-year double-blind trial involving 719 patients with advanced carcinomas of the lung and of the colon. RA-233 treatment was associated with a statistically significant prolongation of survival in patients with non-small cell lung cancer (N-SCLC) limited to one hemithorax and with reduction in mean plasma fibrogen concentration. RA-233 was not toxic. The favorable effects on survival could not be explained by any factor other than the RA-233 treatment. In other tumor categories tested, no differences in survival were observed. These results suggest that RA-233 is useful in the treatment of N-SCLC of limited extent. They also suggest that therapeutic intervention aimed at modified intracellular pathways might constitute a novel investigative approach to the treatment of cancer.

Consolidation and maintenance therapy in multiple myeloma: randomized comparison of a new approach to therapy after initial response to treatment.

A randomized, controlled trial was initiated in 1977 to evaluate the impact of three alternative approaches to consolidation and maintenance therapy after initial maximal response for multiple myeloma. All patients were treated initially with BCNU, cyclophosphamide, and prednisone (BCP) until a designated level of response was achieved. Responders were randomly assigned to either melphalan and prednisone (MP); prednisone, Adriamycin (Adria Laboratories, Columbus, Ohio), azathioprine, and vincristine (PAIV), or no therapy until relapse, then treatment with BCP. Initial response rates were comparable with previous trials. A small number of incremental responses were observed with both MP and PAIV. Survival was the same for all three maintenance approaches and the same as that observed in our previous continuous BCP or MP therapy. Additional or consolidation/maintenance therapy of the type administered here appears to offer little advantage once an initial response has been achieved.

Cytarabine-induced anaphylaxis. Demonstration of antibody and successful desensitization.

An anaphylactic episode occurred in a patient receiving cytarabine (Ara-C) for acute myeloid leukemia. Specific allergy of the patient to cytarabine was demonstrated in vivo by intradermal testing and in vitro by four-hour passive cutaneous anaphylaxis in guinea pigs. Desensitization to cytarabine was successfully performed. This case represents the first known report of both cytarabine anaphylaxis and densensitization, and provides immunologic evidence implicating an allergic reaction to cytarabine.

Criteria for the differentiation of dysfibrinogenemic states.

A large number of families have now been described in whom affected individuals have within their plasmas an abnormal species of fibrinogen (factor I). These defects, presumably examples of the phenomenon of allotypy--i.e., the synthesis of variant forms of a normal protein--have been inherited as autosomal dominant characteristics. In the great majority of cases, clotting is abnormally slow when thrombin is added to the abnormal plasma. Sometimes this defect appears to reside in impaired release of fibrinopeptides by thrombin. In other cases, fibrinopeptide release proceeds normally, but aggregation of fibrin monomers is impeded. In the latter instance, aggregation may be abnormally slow or, once it begins, it may proceed at a normal rate. Curiously, a bleeding tendency is more likely to occur in patients in whom fibrinopeptide release is impaired, while dehiscence of operative wounds rarely complicates dysfibrinogenemias associated with impaired aggregation of fibrin monomers; thrombosis has been described in both groups of patients. Most of the reported cases may be distinguished by functional criteria and by the physicochemical behavior and biochemical nature of the abnormal protein. Additonally, one family has been described in which plasma clots abnormally rapidly upon addition of thrombin, and two others in which crosslinking of fibrin by fibrin-stabilizing factor (factor XIII) is defective.

Fibrin formation: the role of the fibrinogen-fibrin monomer complex.

The process of fibrin formation using highly purified fibrinogen and thrombin was studied using laser fluctuation spectroscopy, a method that rapidly determines particle size in a solution. Two periods in fibrin clot formation were noted: an induction period during which no fibrin polymerization occurred and a period of rapid increase in particle size. Direct measurement of fibrin monomer polymerization and fibrinopeptide release showed no evidence of an induction period. These observations were best explained by a kinetic model for fibrin clot formation incorporating a reversible fibrinogen-fibrin monomer complex. In this model, the complex serves as a buffer system during the earliest phase of fibrin formation. This prevents the accumulation of free polymerizable fibrin monomer until an appreciable amount of fibrinogen has reacted with thrombin, at which point the fibrin monomer level rises rapidly and polymerization proceeds. Clinically, the complex may be a homeostatic mechanism preventing pathological clotting during periods of elevated fibrinogen.

Abnormalities of blood coagulation tests in patients with cancer.

Routine blood coagulation tests were performed on 431 consecutive patients enrolled in a study of the role of anticoagulation in cancer treatment (VA Cooperative Study #75). Two hundred sixteen control patients were treated with standard therapy, and 215 patients were treated with standard therapy plus sodium warfarin. At the time of entry into the study, the most common abnormalities were elevated fibrinogen levels, platelet counts, and fibrinopeptide A levels. Serial studies demonstrated a steady increase in platelet count and fibrinogen levels before death. Anticoagulation lowered FPA levels but had no significant effect on fibrinogen levels, platelet counts, or euglobulin clot lysis times. An unexpected finding was a dramatic increase in fibrin split product levels after institution of anticoagulation (means +/- SEM = 42.6 +/- 116.4 vs. 2.9 +/- 7.0 mg/L in control subjects; P less than 0.02). This study supports the presence of subclinical activation of blood coagulation in most patients with cancer. Moreover, the preferential activation of fibrinolysis in anticoagulated patients suggests a role for a vitamin K-dependent factor(s) in the regulation of fibrinolysis in patients with cancer.

Platelets and malignancy. Rationale and experimental design for the VA Cooperative Study of RA-233 in the treatment of cancer.

Considerable evidence has accumulated in recent years which implicates blood coagulation reactions in the growth and spread of malignancy. In particular, platelets may accumulate on embolic tumor cells and facilitate their adhesion to the endothelium at distant sites perhaps by enhancing blood coagulation reactions. Alternatively, platelets may promote tumor cell proliferation by contributing a growth-promoting factor or through interactions mediated by prostaglandins. Inhibition of tumor growth and spread by platelet-inhibitory drugs has been demonstrated in several experimental tumor systems. Preliminary data suggest that similar effects may be seen in human malignancy. The purpose of this paper is to review relevant literature which provides the rationale for therapeutic trials of platelet-inhibitory drugs in human malignancy and to describe the experimental design for a trial involving one such drug, RA-233, in a recently established VA Cooperative Study.

Comparison of local versus central tumor measurements in a multicenter cancer trial.

Four hundred nineteen solid tumors from 92 patients were measured by a local team consisting of a physician and nurse oncologist or physician's assistant, and centrally by one radiologist. The central radiologist also remeasured 137 tumors on 30 patients to assess intraexaminer agreement. Tumor measurements at specific points in time as well as changes in tumor measurements over time were evaluated. When signed differences were calculated, there was little overall difference between local and central examiners, although three of the eight centers did show a significant difference. However, when absolute differences were calculated, the relative errors of the width times length products ranged from 35 to 55%. Although local and central examiners agreed 75% of the time on change in disease, there was only 42% agreement on the subset of patients who had a remission. In general, the intraexaminer agreement was slightly better than the interexaminer agreement. This study suggests that solid tumor measurements are not particularly reliable, and that survival time remains the most satisfactory endpoint in a cancer clinical trial.

Accrual of patients into a multihospital cancer clinical trial and its implications on planning future studies.

Little information exists on the population of cancer patients from which individual patients are selected for admission to a clinical trial. In fact, most reports of clinical trials of cancer chemotherapeutic agents begin by describing samples of treated patients but neglect to collect data and describe the population from which the samples were taken. In a multi-institutional VA Cooperative Study in which two different cancer treatments were compared, an attempt was made to screen all lung, colorectal, prostate, and head and neck patients seen at participating hospitals prior to randomization to a therapeutic regimen. Of a total of 2687 patients screened, 437 (16.3%) were randomized and 2250 (83.7%) were excluded for 2981 reasons. Protocol reasons were the basis for 68.6% of all exclusions, 21.3% were physician refusals, and 10.1% were patient refusals. The number of patients randomized did not correlate well with number of patients screened across participating centers. Patients admitted to the study tended to be younger and in better health than excluded patients. Overestimates of randomization rates projected initially from published information point to the need for improved screening data in the planning of future studies. Factors such as screening methods, physician acceptance of the experimental approach, number of competing protocols within each center, and cooperation among medical center departments and personnel all are important ingredients in any screening effort.

Tumor conference: the role of continuing medical education.

Tumor conferences and/or boards are established institutions in most hospitals. They function as forums for discussing cancer care. In an attempt to increase attendance of physicians at our tumor conference, CME I credit was granted for a six-month period. Data for a similar period during the prior year were chosen for comparison. Physician attendance as determined on a weekly basis and adjusted for holidays, etc., for the control and study periods was similar (14/control, 13.8/study). We not only did not increase attendance, but of those physicians present, only 42% bothered to sign in for CME I. We concluded that offering CME I credit did not stimulate physician attendance at the tumor conference. This is consistent with recent studies which show that few physicians list "credit" as a motivator of learning.

Opioid analgesic drugs in the elderly.

Much is known about opioid metabolism, which is critical in administering these agents to the elderly. Fear of addiction and tolerance are the major barriers to their use among patients as well as health-care professionals. Addressing these issues early in the initiation opioid therapy will help to alleviate these concerns. Once therapy with an opioid is initiated, the role of renal function is critical. Because many metabolites of the opioids are renally cleared and have activity either in analgesia or as undesired side effects, it is critical to be aware of the creatinine clearance (not just serum creatinine) in the elderly. The initiating doses of the opioids can be equal to that of younger patients, but the clinician should anticipate using a longer frequency of dosing interval or smaller doses during the course of therapy. Methadone, propoxyphene, and meperidine are not recommended for use in elderly people, because of the toxicity of their metabolites. Of all the unwanted effects of the opioids, the most difficult to deal with is that of constipation. Here, an aggressive approach using bowel stimulating laxatives is critical in order to prevent this problem. It is anticipated that a variety of newly formulated opioids will shortly be available for clinical use. Finally, as a better understanding of the neurophysiology of pain is gained, the clinician can anticipate having more analgesic opioids that target their receptors without agonist or antagonist effect on other opioid receptors. This will allow the clinician to better relieve pain with a minimum of unwanted side effects.

Symptomatic management of the older person with cancer.

The older person with cancer is often unable to participate in treatment regimens that a younger person might tolerate. We review the complex reasons why this may be so as well as provide to the reader a brief review of the major symptoms that can cause suffering and treatment regimens that can improve the patient's sense of well being. Palliative care provides the older person with advanced cancer the opportunity to live his or her life to the fullest during that period of life called dying.

Life expectancy, comorbidity, and quality of life. A framework of reference for medical decisions.

The treatment of cancer in the elderly can benefit from increasingly sophisticated methods that measure a patient's quality of life. These measures are both general and cancer specific and herald a new and enlightened approach to patient care. The care of the older patient must be seen in light of what is known about life expectancy, the outcome of treatment, an awareness of comorbidity, and the importance of informed consent and respect for the values and preferences of the individual patient. This article reviews the growing literature on quality of life research in cancer patients.

Current approaches to chronic pain in older patients.

As the population ages, primary care physicians face an increasing number of individuals who suffer from the effects of chronic diseases, including the accompanying chronic pain. This article reviews the common causes of pain in the elderly and suggests a system for assessing its severity. Five different approaches to treating pain in this population are outlined, as are guidelines for managing the potential side effects of treatment.

On the 10th anniversary of the organization of the American Academy of Hospice and Palliative Medicine (AAHPM): the first 10 years.

The American Academy of Hospice and Palliative Medicine (originally chartered as the Academy of Hospice Physicians in 1988) is an organization of physicians devoted to advancing hospice and palliative medicine in the United States. The academy's mission is "physicians dedicated to promoting quality hospice care for the terminally ill through medical education, research, and training." The academy obtained specialty recognition from the AMA in 1996 and became the first physicians' group to publish its position on physician-assisted suicide in 1991 and again in 1997.

Pain management for the geriatric patient.

Pain is a common and complex problem in the geriatric population. Successful pain management in this patient population requires a comprehensive approach involving both pharmacologic and nonpharmacologic interventions.

The role of chemotherapy and adjuvant therapy in the management of colorectal cancer.

This review of the current literature related to the use of chemo- and adjuvant chemotherapy in colorectal carcinoma emphasizes the present dilemma in caring for people affected with this disorder. Adjuvant chemotherapy using combinations of 5-fluorouracil and levamisole clearly prolong survival, albeit, for only a small group of individuals. However, for the older person, this regimen may be associated with unacceptable toxicity and a physician's inability to deliver a dose-intensive course, as the authors currently understand it. Although quality of life is a clear concern of many older persons, little currently is available to evaluate this parameter during chemotherapy. It remains an important issue to address in the elderly person, because 35% of individuals found to have colorectal carcinoma are older than 65 years. Hopefully, better staging by incorporating molecular biologic techniques will assist in the effort to uncover the best regimens.