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Ethical issues are presented concerning the appropriate use of a fee-for-service strategy to fund clinical research assessing preventive complementary medicine approaches, particularly the effectiveness of dietary supplements for disease prevention. Reasons for the need for such an alternative funding approach are identified and historical precedents are noted. Presuming a priori key desiderata of doing no harm, not taking advantage of the ill, and pursuing recognized useful purposes, six key ethical questions from the relevant literature are identified and discussed. Arguments are advanced that there is a sound rational, ethical basis (1) to ask patients to pay for clinical experimentation in the focused area of supplement-directed disease prevention; (2) to accept the reality that those who cannot pay may not participate; (3) to permit moderate profit from the ongoing research; (4) to allow researchers to receive fees for their support of such clinical research; (5) to pursue this alternative funding strategy in addition to conventional sources; and (6) to expect that patients can give informed consent in such settings. It is demonstrated that patient-funded research has been an integral component of clinical research for decades and that there is no inherent reason why explicit patient payment of fees need be less ethical than any other commonly accepted funding models. Accordingly, an ethical case is made for the appropriateness and value of significantly expanded fee-for-service-funded research within a complementary medicine context, particularly the assessment of dietary supplements for disease prevention. [ABSTRACT FROM AUTHOR]

Farmers can counteract global warming by drawing carbon dioxide from the air into agricultural soils by building up humus. Humus programs were developed to motivate farmers for even more humus formation (= carbon sequestration) through an additional financial incentive. These programs are still at an early stage of development, which is why the number of participating farmers and research work is still low. This study is the first to analyze the willingness of German farmers to participate in hypothetical humus programs. The results of a discrete choice experiment show that a (higher) threshold for the payout of the premium, regional (rather than field-specific) reference values, and the risk of repayment clearly discourage farmers from participating. Program providers must more than double the premium (set at around 240 € per hectare and 0.1% humus increase) to maintain farmers' willingness to participate despite a payout threshold. Regional reference values and an additional premium/repayment system would lead to an increase in the premium of around 20 € per hectare in order to keep the willingness to participate at the same level. The motivation to build up humus, the desire to maximize subsidies, and a higher livestock density have a positive influence on farmers' decision to participate. Farm size and risk attitude have an impact on farmers' preferences for program design. The study is relevant for policymakers and non-governmental organizations concerned with carbon management, as our findings highlight pathways for efficient, targeted designs of humus programs and carbon sequestration policies., (© 2024. The Author(s).)

Mitigating climate change by sequestering carbon in agricultural soils through humus formation is a crucial component of sustainable agriculture. Humus programs that are designed to incentivize farmers to build more humus are still recent innovations, so current knowledge about farmers' motivation to participate is limited. This study examines the adoption of non-governmental humus programs to promote carbon sequestration by analyzing farmers' willingness to participate in humus programs and influential factors. We specifically investigate behavioral factors underlying farmers' adoption of humus programs using the Theory of Planned Behavior. To this end, we collected data using an online survey with 190 German farmers and applied partial least squares structural equation modeling. The results show that (i) perceived economic benefits, (ii) the actions of fellow farmers, and (iii) farmers' sense of responsibility with regard to climate change have a statistically significant influence on farmers' intention to participate in a humus program. In contrast, the perceived ecological benefits, political pressure, the possibility of establishing humus-building measures, and prior knowledge of humus programs have no statistically significant influence. Our findings suggest that farmers' decision to participate in humus programs is strongly influenced by the financial benefits, but the actions and thoughts of other farmers, as well as their own moral claims regarding climate change, also play a crucial role. We found that farmers lack knowledge about the registration and general functioning of humus programs, which can currently be one of the biggest barriers to participation in such initiatives., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

We report 10 years' follow-up of the previously described family with a novel mutation of the KCNA1 gene. The family consisted of 3 affected boys (first seen at ages 3, 11, and 12) and their affected mother and asymptomatic father and sister. They clinically presented with diffuse myokymia, muscle cramps, and lower limb spasticity without ataxia, but episodic ataxia developed later during adolescence and early adulthood. Long-term follow-ups of families with known KCNA1 gene mutation are rarely mentioned in the literature. Treatment with carbamazepine, 600 to 800 mg daily resulted in cessation of muscle cramps and marked improvement of lower leg symptoms. In the youngest child, after 2 years carbamazepine had to be changed to oxcarbazepine because of side effects. Carbamazepine and oxcarbazepine are both effective in treatment of symptoms related to KCNA1 gene mutation. Symptoms will reoccur if treatment is stopped and there is variability of symptom severity between family members.

Olanzapine is an atypical antipsychotic drug that infrequently has been reported to cause seizures and myoclonus despite a small proconvulsant risk. This is the first report of generalized myoclonus induced in a patient who had been maintained on low dose olanzapine for over seven years without any change in her dose. Olanzapine was discontinued, and the myoclonic jerks completely resolved within 48 h., (Copyright © 2011. Published by Elsevier B.V.)

Although mammography can aid in the early detection and prevention of breast cancer, many women do not receive annual mammograms. It remains unclear whether anxiety about breast cancer inhibits or promotes mammography rates. The way in which women regulate their anxiety (ie, level of experiential avoidance) may play a role in predicting mammography adherence. A community sample of women (N = 84) completed a questionnaire which assessed mammography rates, experiential avoidance, and breast cancer anxiety. The results suggest that, while controlling for breast cancer anxiety, experiential avoidance (β = .31, p < .01) significantly predicted mammography rates. When examining experiential avoidance as a moderator, a multiple regression analysis approached significance (R2 Δ = .04, p = .07), suggesting that a woman's level of experiential avoidance influences the relationship between anxiety and mammography. These findings will help enable health care practitioners to better identify women at risk of non-adherence to mammography recommendations.

Background: A pilot safety study of focused microwave phased array thermotherapy in the treatment of primary breast carcinomas was conducted., Methods: Ten patients with breast carcinomas beneath the skin surface that ranged in maximal clinical size from 1 to 8 cm (mean, 4.3 cm) were treated with the breast compressed in the prone position. We planned to deliver a tumor thermal dose equivalent to 60 minutes at 43 degrees C. Breast imaging and pathology data were used to assess efficacy., Results: For the 10 patients, the mean tumor equivalent thermal dose was 51.7 minutes, the mean peak tumor temperature was 44.9 degrees C, and the mean treatment time was 34.7 minutes. Ultrasound imaging demonstrated a significant reduction in tumor size (mean, 41%) 5 to 18 days after thermotherapy in 6 (60%) of 10 patients. A significant tumor response on the basis of reduction in tumor size or significant tumor cell kill occurred in 8 (80%) of 10 patients., Conclusions: With sufficient skin cooling, delivery of focused microwave phased array thermotherapy is safe in treating breast carcinomas when used alone, and some potential efficacy was demonstrated at the tumor thermal doses administered. Increased tumor thermal dose efficacy studies in larger patient populations for improved breast conservation should be investigated.

This randomized, prospective, placebo-controlled clinical trial compares the influence on nutritional status and survival of hydrazine sulfate with placebo addition to cisplatin-containing combination chemotherapy in patients with unresectable non-small-cell lung cancer (NSCLC). The trial consisted of 65 patients with advanced, unresectable NSCLC who had had no prior chemotherapy, were at least partially ambulatory (Eastern Cooperative Oncology Group [ECOG] performance status [PS] level 0-2), and who had adequate hematologic, renal, and hepatic function. All patients received the same defined combination chemotherapy (cisplatin, vinblastine, and bleomycin) and the same defined dietary counseling with the addition of either three times daily oral hydrazine sulfate (60 mg) or placebo capsules. Hydrazine sulfate compared with placebo addition to chemotherapy resulted in significantly greater caloric intake and albumin maintenance (P less than .05). Considering all patients, survival was greater for the hydrazine sulfate compared with placebo group (median survival, 292 v 187 days), but the difference did not achieve statistical significance. In favorable PS patients (PS 0-1), survival was significantly prolonged (median survival, 328 days v 209 days; P less than .05) for hydrazine sulfate compared with placebo addition. In a multifactor analysis, PS, weight loss, and liver involvement were the final variables. Objective response frequency and toxicity were comparable on both arms. Hydrazine sulfate may favorably influence nutritional status and clinical outcome of patients with NSCLC. Further definitive studies of hydrazine sulfate addition to therapeutic regimens in NSCLC are warranted.

To assess the antineoplastic potential of vitamin K compounds, the effects of vitamin K3 (menadione), vitamin K1 (phylloquinone), and warfarin on L1210 murine leukemia cell growth were studied in a flask culture system. When the cytotoxic potential of vitamin K3 was recognized, the effects of vitamin K3 on human tumor colony formation were studied in 34 tumor explants using a soft agar (clonogenic) assay system. Complete inhibition of L1210 growth in flask culture was achieved at concentrations of 200 micrograms/ml of warfarin, 75 micrograms/ml of vitamin K1, and 4 micrograms/ml of vitamin K3. Combined use of vitamin K and warfarin enhanced cytotoxicity because a concentration of 1 micrograms/ml of vitamin K3 together with 70 micrograms/ml of warfarin resulted in nearly complete inhibition of L1210 growth. Comparable inhibition of growth was seen against malignant murine cell lines in the soft agar assay system, where greater than 70% decrease in colony formation was seen with vitamin K3 at concentrations of 6.4 micrograms/ml for L1210 leukemia and 1 microgram/ml for HII4E hepatoma lines. Vitamin K3 was also cytotoxic in the same dosage range when tested in vitro against the 34 human tumor explants in the soft agar assay system. Tumor types evaluated included adenocarcinoma of the breast (16 patients), ovary (five), colon (two), stomach (two), kidney (two), and unknown primary (two); squamous cell carcinoma of the lung (two); melanoma (one), transitional cell carcinoma of the bladder (one); and hepatocellular carcinoma (one).(ABSTRACT TRUNCATED AT 250 WORDS)

One hundred and thirty-four patients with advanced malignant disease were treated with 496 infusions of high-dose methotrexate (HD-MTX) followed by citrovorum factor rescue. Most patients had failed to respond to previous combination chemotherapy. The overall response rate was 29% with 33 partial responses and six complete responses observed in patients with a variety of tumors. Plasma MTX levels were monitored in all patients during each course of therapy in order to identify those patients with delayed plasma MTX clearance. Patients with abnormally slow rates of plasma MTX decay received escalated doses of citrovorum factor rescue in order to prevent drug-induced toxicity. In general, during this study HD-MTX was well-tolerated. Because serious toxicity was neither frequent, severe, nor unpredictable, its use was not limited. HD-MTX should now be evaluated in well-designed controlled clinical trials to compare its antitumor activity to that of conventional- or standard-dose MTX regimens in diseases where HD therapy appears to have efficacy.

Of 157 consecutive patients who had histologically diagnosed hepatocellular carcinoma, 52 with a good performance score, bilirubin less than 2 mg/dl, and absence of bloody ascites were treated with a 75-mg/m2 dose of doxorubicin (unadjusted for hepatic function) every 3 weeks in a prospective trial. Forty-six patients were treated in West Africa and six in Southern California. No complete responses were seen and only six patients (11%) achieved partial objective responses. Plasma concentrations of doxorubicin and doxorubicinol (adriamycinol) were determined at four selected time points for up to 72 hours, corresponding to the terminal phase of disposition in eight African patients. The African patient results were compared to those seen in North American patients with hepatocellular carcinoma and other malignancies. In African patients with hepatocellular carcinoma, terminal half-life of doxorubicin was prolonged at 39.8 +/- 15.9 hours. The ratios of the corresponding concentration X time values of doxorubicinol to doxorubicin, which reflect the overall metabolite to parent drug ratio, ranged from 0.7 to 4.6, with a mean ratio of 2.03 +/- 1.20 in the African patients with hepatocellular carcinoma compared to a mean ratio of 0.76 +/- 0.31 in North American patients with other malignancies. Pharmacokinetic findings in hepatocellular carcinoma patients in North America and Africa were similar, reflecting elevation and prolongation of doxorubicinol metabolite relative to doxorubicin in the plasma of patients with this disease from both areas. We conclude that: (a) doxorubicinol disposition is altered in African as well as North American patients with hepatocellular carcinoma; and (b) even when given in full dose to patients with favorable prognostic features, iv doxorubicin has only limited activity against hepatocellular carcinoma.

Analysis of controlled and uncontrolled published papers in clinical cancer therapy has revealed differences in patient data handling, which may reflect both the inherent biases of patient selection for uncontrolled studies and the primary purpose of such studies. A distinction between drug-data oriented research and patient oriented research was advanced to explain these results. If comparable results are to be developed, we urge controlled trials at all phases of treatment development.

Fifty-five patients were sensitized to dinitrochlorobenzene (DNCB). Two weeks later they were challenged. The minimal concentration yielding 2+ reactivity and one dilution above and below were then applied to the anterior chest wall on both the operated and nonoperated sides. Using multinomial chi-square statistical analysis, we found that the operated and nonoperated sides evidenced equal reactivity. Futhermore, the absence of axillary lymph nodes did not diminish the reactivity in the operated area. These data support the contention that maintenance of local cellular immunity, as assessed by DNCB skin test reactivity, is systemic and counters the argument that regional lymphadenectomy impairs local and/or systemic cellular immunity.

Thirty-eight patients with advanced cancer and weight loss were tested in a prospectively randomized, double-blind, placebo-controlled trial to evaluate the influence of hydrazine sulfate on carbohydrate metabolism in cancer cachexia. All patients had an initial 3-day inpatient metabolic evaluation including: standard 5-hr p.o. glucose tolerance test, hormone studies, and total glucose production by infusion of [6-3H]glucose. After 30 days of treatment with capsules containing either placebo or hydrazine sulfate in a 60-mg, 3 times/day dosage, inpatient evaluation was repeated. A total of 62 metabolic inpatient evaluations were performed. The pretreatment characteristics of age, sex, prior therapy experience, nutritional parameters and tumor types were comparable in placebo and hydrazine treatment groups. On initial evaluation, abnormal glucose tolerance and increased glucose production were frequently seen. Serial assessment of glucose tolerance showed no improvement after 30 days of placebo treatment. However, the glucose tolerance was significantly improved in patients receiving 30 days of hydrazine sulfate [2-hr glucose; initial 169 +/- 24 (S.E.) mg/dl versus final 128 +/- 12 mg/dl; p less than 0.05]. In addition, the rate of total glucose production was significantly decreased after 30 days of hydrazine sulfate compared to placebo treatment (2.46 mg/kg/min versus 3.07 mg/kg/min, respectively; p less than 0.05). Toxic effects of hydrazine sulfate were minimal. Our results suggest that hydrazine sulfate can influence the abnormal carbohydrate metabolism associated with weight loss in patients with cancer.

In clinical studies performed during 111 infusions of high dose methotrexate (MTX) we have evolved a clinical and laboratory protocol which permits such therapy without prohibitive risk to the patient. The plasma MTX data obtained indicate that pharmacokinetic disposition is dose related during these infusions and that such data are useful in identifying patients at risk from serious toxicity.

The methotrexate (MTX)-plasma concentrations of 172 high-dose infusions over the range of 50-200 mg/kg were measured over the 72-hour period following the beginning of infusion. Pharmacokinetic analysis shows that a biexponential function adequately describes the plasma decay for all doses. The distribution of plasma clearances over the patient population at a given dose has been characterized by a biexponential clearance function and associated time-dependent variance. It is found that when each of the plasma clearance functions are scaled by their respective dose, the 1 SD bands about the resulting unit dose curves overlap throughout their time ranges and are therefore insignificantly different from one another. Thus, the plasma clearance over the 50-200-mg/kg range may be represented by a single dose-scalable biexponential model with half-lives of 1.8 +/- 0.1 and 8.4 +/- 0.5 hours. For a given maximum allowable plasma-MTX level (eg, 10(-5) M at 24 hours), the variance of the clearance distribution is shown to predict the expected fraction of patients who will require intensified rescue. Urinary clearance has been determined at 104 +/- 8 ml/minute over the dose range of 50-300 mg/kg and only 60% of the MTX was excreted in the urine by 72 hours.

Hydrazine sulfate was evaluated using 24-hour dietary recalls and body weight determinations before and after 30 days of either placebo or hydrazine (60 mg, 3 times/d) oral administration in 101 heavily pretreated cancer patients with weight loss. After 1 month, 83% of hydrazine and only 53% of placebo patients completing repeat evaluation maintained or increased their weight (P less than 0.05). In addition, appetite improvement was more frequent in the hydrazine group (63% versus 25%, P less than 0.05). Although caloric intake was only slightly greater in hydrazine-treated patients, an increased caloric intake was more commonly associated with weight gain in patients receiving hydrazine compared with those receiving placebo (81% versus 53%, respectively). Hydrazine toxicity was mild, with 71% of patients reporting no toxic effects. Hydrazine sulfate circulatory levels were obtained from a subset of 14 patients who completed 30 days of treatment, with a single sample obtained in the morning at least 9 hours after the last dose. Mean maintenance hydrazine sulfate levels, determined using a spectrofluorometric assay, ranged from 0 to 89 ng/ml (mean 45 +/- 16 ng/ml). These data, which demonstrate an association between 1 month of hydrazine sulfate administration and body weight maintenance in patients with cancer, suggest future clinical trials of hydrazine sulfate are indicated to definitively assess its long-term impact on important clinical outcome parameters in defined cancer populations.

Satisfactory chemotherapeutic management of malignant melanomas in advanced stages must await development of more active agents and combinations of them than are presently available. The development of entirely new means of treatment by hormones, heat, and adjuvants like amphotericin B may improve the efficacy of currently available agents.

Local anesthetics may influence cell membrane structure and permeability. An established human melanoma cell line (SHG) derived from malignant ascites was used to evaluate the growth-inhibitory effects of local anesthetics (procaine and lidocaine) as well as of doxorubicin at incubation temperatures of 37.5 degrees C and 40 degrees C. In this system, procaine and lidocaine inhibited growth at 0.82 mg/ml and doxorubicin inhibited growth at 28 ng/ml. Noninhibitory concentrations of procaine (0.64 mg/ml) when combined with noninhibitory concentrations of doxorubicin (10 ng/ml) resulted in marked growth inhibition. Incubating temperatures of 40 degrees C enhanced all effects of procaine and doxorubicin on cell growth. These results suggest that clinically achievable concentrations of local anesthetics enhance doxorubicin cytotoxicity.

Intense muscle localization of Tc-99m MDP to upper extremity musculature was noted three days following weight lifting exercises. This phenomenon is due to an unknown mechanism although several causative factors have been suggested.

Thirty patients with operable epidermoid carcinoma of the head and neck were treated with intravenous high dose methotrexate and leucovorin rescue prior to resection. Their clinical courses were compared with those of thirty randomly selected patients matched for tumors site and clinical stage who were treated by surgery alone. No medical or surgical complications associated with methotrexate were encountered. An objective decrease in tumor size (primary lesion or nodal metastases) was noted prior to resection in twenty-three patients (77 per cent). The number of recurrences in the two groups was similar. However, these was a significantly greater disease-free interval in the methotrexate-treated patients (p less than 0.05). No significant differences in survival have been noted to date between the two groups. In view of the absence of complications, the regressions in tumor size, and the increase in postoperative disease-free interval in this trial, evaluation as preoperative adjuvants of higher doses of methotrexate and of other chemotherapeutic agents in combination with methotrexate appears warranted.

Neurologic complications of systemic cancer may result from metastatic spread of tumor to the central nervous system, from paraneoplastic effects of peripheral tumor, or from side effects of anticancer therapy. This article outlines currently available data on clinical presentations of these complications and diagnostic modalities for their recognition, data which may help the clinician ameliorate the often devastating sequelae of these neurologic complications.

To evaluate the role of cisplatinum in the treatment of advanced non-small cell lung cancer, 48 patients received either a doxorubicin (adriamycin) 50 mg/m2 I.V., cyclophosphamide 300 mg/m2 I.V., lomustine (CCNU) 50 mg/m2 p.o., vincristine (oncovin) 1.2 mg/m2 I.V. (ACCO) combination or the same drugs plus cisplatinum 50 mg/m2 I.V. (PACCO) in a prospective sequential trial. No patient had received prior chemotherapy. Patients receiving the two regimens were comparable with regard to median age, performance status, histologic subtype, disease extent, and weight loss. Objective response frequency was only 5% in the initial 20 patients receiving ACCO treatment compared to a response frequency of 28% (7% complete) in the 28 patients receiving cisplatinum in the PACCO treatment arm (p less than 0.06). Patients achieving objective response lived significantly longer than nonresponders (9.1 months vs. 3.8 months, p less than 0.05). Although median survival was similar on the two regimens (6.1 months for ACCO vs. 7.6 months for PACCO), more than four times as many patients were alive after 1 year in the PACCO treatment group (24% vs. 5%). Predominant toxicity consisted of moderately severe nausea and vomiting (63% on PACCO vs. 34% on ACCO, p less than 0.05) and myelosuppression with WBC less than 3,000/mm3 occurring in the majority of patients on both regimens. These results suggest cisplatinum addition to a doxorubicin, cyclophosphamide, lomustine, and vincristine combination may be associated with increased 1-year survival in the non-small cell lung cancer patient population.

The deoxyuridine (dU) suppression test, which estimates the activity of the de novo pathway to DNA synthesis from dU, was evaluated as a predictor of antimetabolite growth inhibition. Observations of growth inhibition were made using flask cell culture and soft agar clonogenic assay and correlated with results of the rapidly performed dU suppression test in human (SK-L7) leukemia cells, in methotrexate-sensitive and -resistant murine (L1210) leukemia cells, and in human tumor explants. The concentration of methotrexate resulting in a positive dU suppression test was closely correlated with the methotrexate concentrations required for growth inhibition in flask and soft agar culture systems. The fact that the dU suppression test can be rapidly interpreted in 4 hours compared to the longer period required for clonogenic assay suggests that further evaluation of this procedure as a rapid predictor for clinical antimetabolite response is warranted.

We investigated the mechanism of antitumor activity of the water-soluble derivative of menadione, menadione sodium bisulfite (vitamin K3), versus murine leukemia L1210. Vitamin K3, in concentrations greater than 27 microM, caused time- and concentration-dependent depletion of the acid-soluble thiol (GSH) pool. Maximal GSH depletion to 15% of control occurred at 45 microM vitamin K3. Vitamin K3-mediated GSH depletion and vitamin K3-mediated growth inhibition were abrogated by coincubation with 1 mM cysteine or 1 mM reduced glutathione but not by 1 mM ascorbic acid or 180 microM alpha-tocopherol. Low concentrations of vitamin K3 (9-27 microM) elevated both the GSH pool and the total glutathione pool, the latter to a greater degree. Vitamin K3 also caused an increased rate of superoxide anion generation by L1210, maximal at 45 microM vitamin K3 (300% of control), and a concentration-dependent depletion of the reduced nicotinamide adenine dinucleotide phosphate (NADPH) and total nicotinamide adenine dinucleotide phosphate (NADP) pools. Forty-fifty % depletion of the NADPH pool occurred after exposure to 27 microM vitamin K3 and 100% occurred at 36 microM vitamin K3; 27 microM vitamin K3 is a nontoxic concentration of vitamin K3. Loss of NADPH and total NADP was prevented by coincubation with 1 mM cysteine but not by coincubation with ascorbic acid or alpha-tocopherol. We conclude that tumor cell growth inhibition by vitamin K3 is modulated by acid-soluble thiols and may be caused by GSH pool and/or NADPH depletion. Toleration of partial NADPH depletion by L1210 cells may indicate that a threshold level of NADPH loss of greater than 50% is necessary for toxicity. NADPH depletion may be a toxic effect common to quinone drugs. Equitoxic concentrations of vitamin K3, phylloquinone, lapachol, dichlorolapachol, and doxorubicin caused L1210 NADPH pools to deplete to 30 +/- 10 (SD), 60 +/- 10, 60 +/- 11, and 80 +/- 12% of control, respectively. In contrast, GSH depletion may not be a common mechanism of toxicity. Of these quinones, only vitamin K3 caused significant GSH depletion when studied in equitoxic concentrations.

Diagnostic and prognostic characteristics of 121 North American patients with hepatocellular carcinoma seen in one metropolitan area over a 6-year period were assessed using multivariate analysis. Presenting symptoms commonly included abdominal pain (53%) or mass (34%), anorexia (31%), and ascites (20%); however, the ability to make an early diagnosis was complicated by a variety of unusual symptoms accounting for 25% of presentations. While cirrhosis (63%) and hepatitis B surface antigen (HBsAg) positivity (52%) were common associated findings, the majority of patients (67%) had no prior diagnosis of liver disease. Despite the vascular nature of these malignancies, percutaneous biopsy procedures performed in 66 patients provided diagnostic material in over 85% of cases with little morbidity. Histologic diagnosis was made by blind percutaneous biopsy (41 done, 83% positive), peritoneoscopy with directed percutaneous biopsy (25 done, 88% positive), laparotomy (42 done, 98% positive), or autopsy (19). Percutaneous hepatic biopsy procedures were associated with no mortality and rare bleeding (three cases). Overall median survival was only 18 weeks; multivariate analysis indicated increased bilirubin or presence of pulmonary metastases adversely influenced outcome. Unexpectedly, patients younger than 45 years of age had a significantly (P less than 0.01) greater survival (median, 40 versus 9 weeks) than did older patients with this disease. We conclude: (1) hepatocellular carcinoma can be rapidly and safely diagnosed using percutaneous biopsy procedures; (2) North American patients with hepatocellular carcinoma younger than 45 years of age have a more favorable prognosis.

Twenty-five patients with advanced measurable adenocarcinoma of the colon were treated with 5-fluorouracil (FUra), 15 to 20 mg/kg/week i.v., plus warfarin p.o. at a dosage which maintains therapeutic levels of anticoagulation. Sixty-four % of patients achieved either objective response (20%) or stable disease (44%). Overall median survival was 19.2 months. Three patients (all with intraluminal lesions) developed gastrointestinal blood loss requiring transfusion and discontinuation of anticoagulation. The interaction between warfarin and FUra as measured by plasma levels was investigated in seven rabbits and three patients. Plasma samples were obtained for 2 hr after FUra administration, both before and after anticoagulation with warfarin. FUra was measured by gas chromatography, and warfarin was assayed using a thin-layer chromatographic fluorescence method. In rabbits, prolongation of FUra plasma t1/2 was seen with high (0.6 mg/kg/hr) but not low (0.025 mg/kg/hr) rates of warfarin infusion. In patients, FUra t1/2 was not changed by therapeutic warfarin anticoagulation. Thus, (a) plasma clearance interaction between FUra and warfarin does not occur in patients receiving therapeutic levels of anticoagulation; (b) FUra and warfarin anticoagulation can be safely given and frequently result in stable disease status for patients with advanced colon cancer. Further trials of this combination are warranted in adenocarcinoma of the colon.

The Mycosis Fungoides Cooperative Group has been following patients with cutaneous T-cell lymphoma, including mycosis fungoides and the Sézary syndrome variant. Previous analyses identified the extent of skin involvement and the number of sites of clinically enlarged lymph nodes as important prognostic variables. These two variables were used to classify 340 patients into four clinical stages. Repeat analysis based on additional followup data shows the usefulness of this clinical staging system for identifying patients with differing survival experience. An alternative grouping suggested by fitting a survival model to the data also has been studied. Staging systems based only on skin involvement and lymph nodes are recommended for general use because the information needed is readily available, requiring only physical examination.