Exposure to domestic cats: risk factor for Pasteurella multocida peritonitis in liver cirrhosis?

Pasteurella multocida is most commonly associated with acute skin and soft tissue infections following an animal bite or scratch. Peritonitis caused by P. multocida in patients with cirrhosis is rarely reported. We present a case of spontaneous bacterial peritonitis with P. multocida in a patient with cirrhosis, squamous cell cancer of the head and neck, and nontraumatic domestic cat exposure. Nasopharyngeal colonization with P. multocida, with subsequent transient bacteremia and seeding of the peritoneum in immunocompromised (particularly cirrhotic) cat-owners, could play an important pathogenetic role in the development of spontaneous bacterial peritonitis. A review of the literature showed that in nine of 13 patients with cirrhosis and P. multocida peritonitis, exposure to domestic animals was reported. The mortality rate is high in this setting, even with prompt antibiotic treatment. Preventive strategies for immuno-compromised patients should include minimization of animal contact, especially cats, which have a high carriage rate (70-90%) of P. multocida.

A phase I trial of combination fludarabine monophosphate and chlorambucil in chronic lymphocytic leukemia: a Southwest Oncology Group study.

Fludarabine monophosphate is a new antimetabolite with demonstrated activity in chronic lymphocytic leukemia (CLL). We have investigated the practicality of utilizing fludarabine in combination with chlorambucil in a disease-specific phase I trial. Twenty-one patients with advanced and previously treated, relapsed or refractory CLL were treated with chlorambucil plus fludarabine. Chlorambucil was given day 1 at 15 or 20 mg/m2 per os and fludarabine days 1-5 at 10, 15, or 20 mg/m2 intravenously, every 28 days. We concluded that with chlorambucil 15 mg/m2, the maximum tolerated dose for fludarabine was 20 mg/m2 in this patient population with this scheduling. Dose-limiting toxicity was thrombocytopenia. A low incidence of peripheral neuropathy, rash, pulmonary fungal infection, and acute tumor lysis syndrome was also encountered. Although responses were observed, it was impossible from this study to determine whether the combination was better than fludarabine alone in this heavily pretreated population. This study does, however, demonstrate the feasibility of exploring the utility of such a combination in previously untreated patients. An intergroup phase III trial utilizing this combination has been initiated.

Evaluating selected internship candidates and their subsequent performances.

The authors compared selection criteria with subsequent performances of housestaff on a medical service over a 13-year period. The selection criteria studied included class rank, grades in the four major clinical clerkships, scores on the National Board of Medical Examiners Part I examination, Alpha Omega Alpha membership, and numerical ranking by the intern selection committee. Only the last criterion correlated significantly (p = .0015) with subsequent housestaff performance. The synthesis of all available information by an intern selection committee is valuable in choosing candidates with future promise.

Coumarin necrosis of the penis.

Coumarin-induced necrosis of the skin and subcutaneous tissue is an uncommon but well recognized complication of anticoagulant therapy. Although any area of skin may be involved necrosis of the penis is rare. We report a case of penile necrosis associated with coumarin therapy and review the literature.

Phase II trial of 9-beta-D-arabinofuranosyl-2-fluoroadenine 5'-monophosphate in non-Hodgkin's lymphoma: prospective comparison of response with deoxycytidine kinase activity.

A phase II study of 9-beta-D-arabinofuranosyl-2-fluoroadenine 5'-monophosphate was done in non-Hodgkin's lymphoma with a loading dose/continuous intravenous infusion schedule, consisting of a 20 mg/m2 loading dose followed by a continuous i.v. infusion of 30 mg/m2/24 h for 48 h. The loading dose was held constant while the continuous i.v. dose was escalated or decreased as appropriate for toxicity. Twenty-six patients were entered on the study; 25 are evaluable for response. The patients' median age was 61 years (range 25 to 73); their mean performance status was 1.1. They had received a mean of 2.6 prior chemotherapeutic regimens, and six also had prior radiation therapy. There was one complete response lasting 9+ months, and there were seven partial responses lasting 20, 13, 11, 11, 10, 5, and 2 months (response rate 32%). Toxicity was acceptable and consisted mainly of myelosuppression. 9-beta-D-arabinofuranosyl-2-fluoroadenine 5'-monophosphate is dephosphorylated in vivo and then is thought to be activated intracellularly to 9-beta-D-arabinofuranosyl-2-fluoroadenine 5'-triphosphate. The rate-limiting enzyme is deoxycytidine kinase. Deoxycytidine kinase activity was determined on pretreatment tumor samples for correlation with response. There was no difference between the values for responders and nonresponders. There was a trend for higher values in more malignant histological subtypes.

Phase I trial of homoharringtonine administered by prolonged continuous infusion.

Cephalotaxine alkaloids have been extensively used in the Peoples Republic of China for treatment of acute leukemias and solid tumors (Yu-hua, L., Shu-fen, G., Fu-ying, Z., Shu-zhi, X., and Hui-lin, Z. Chin. Med. J., 96: 303-305, 1983). Several Phase I trials of homoharringtonine have been completed in the United States using either bolus administration or continuous infusion over a 5-day period. The major toxicities have been hypotension following rapid administration and myelosuppression when lower doses are infused over 5 to 7 days. None of these studies, however, reproduce the schedule used in China which is i.v. infusion of approximately 1 mg/day over 4-8 h for a period of 14-28 days or more, followed by a rest period of approximately 7-14 days. This study more closely reproduces that schedule as a Phase I trial by decreasing the daily dose of homoharringtonine and using a continuous infusion schedule to allow escalation of total days of treatment. Forty-eight patients entered the study. The final recommended dose of homoharringtonine is 1 mg/m2/day for 30 days followed by a 2-week rest period. The dose limiting toxicity of myelosuppression was severe and prolonged in some patients. Nonhematological toxicities were minimal and generally well tolerated. Patients should be followed with at least weekly blood counts and treatment interrupted pending full marrow recovery if the granulocyte count falls below 1,000/mm3 or the platelet count falls below 100,000/mm3.

Mechanisms for the oxidation of reduced gluthathione by stimulated granulocytes.

We have reported previously that human granulocytes have an irreversible fall in their endogenous reduced soluble sulfhydryls following zymosan stimulation. In the present study, we demonstrate that stimulated granulocytes release one or more reactive oxygen species (ROS) with the capacity to oxidize reduced glutathione (GSH). One or more of these compounds is stable enough to be detected in the supernatant. The formation of these stable oxidants appears to require H2O2 and heme or a heme-containing enzyme. However, once formed, the compound reacts with GSH without these factors. The ROS is not superoxide or hydroxyl radical, since neither superoxide dismutase nor the hydroxyl scavengers, mannitol and benzoic acid, change the rate of the reaction. Methionine has recently been demonstrated to be oxidized to a sulfoxide by a reactive oxygen species that is dependent on H2O2 and heme for its production. We found that methionine could directly react with the same ROS that degrades GSH. The ROS also has the capacity to oxidize iodide and fix halogen to proteins. Our data indicate that stimulated granulocytes release a ROS with the capacity to oxidize GSH, react with methionine, and oxidize and fix I- to protein. The compound, therefore, appears dependent on H2O2 and the myeloperoxidase system for its production, and is either hypochlorous acid (HOCI) or a compound derived from HOCI, such as a chloramine. The capacity of GSH to react with this ROS suggests an additional role for this tripeptide in cellular protection against oxidant injury.

Phase I trial of homoharringtonine.

Homoharringtonine is one of a group of cephalotaxine esters reported by the Chinese to have significant antitumor efficacy, with particularly good activity in human leukemias. Preclinical antitumor activity against P388 leukemia, colon 38 carcinoma, and mammary carcinoma led to phase I trials which are currently nearing completion in this country. The phase I study reported here used a single infusion of homoharringtonine over 90 minutes given every 21 days. Dose-related and life-threatening hypotension, without significant myelosuppression, was the dose-limiting toxic effect. The mechanism of hypotension is not understood but it is not related to cardiac arrhythmias. Myelosuppression was not seen regularly. We do not recommend this schedule for phase II trials.

Improved complete remission rates and survival for patients with large cell lymphoma treated with chemoimmunotherapy. A Southwest Oncology Group Study.

Between 1974 and 1977, 652 patients with non-Hodgkin's lymphoma without prior chemotherapy were randomized to 1 of 3 combination chemotherapy programs designed to induce complete remission (CR): COP-bleomycin (180 patients), CHOP-bleomycin (232 patients) or CHOP plus immunotherapy with Bacillus Calmette Guerin (BCG) (240 patients). With mature follow-up, the major effect of BCG immunotherapy was observed in patients with large cell lymphomas (diffuse or nodular "histiocytic") and not in other common lymphoma subtypes. CR rate for 65 patients with large cell lymphoma treated with CHOP-BCG was 68% compared to 48% in 61 patients treated with CHOP-bleomycin (P = 0.02) (two-tailed test) or 44% for 45 patients treated with COP-bleomycin (P = 0.02). CR duration for both CHOP-based regimens was similar and superior to that produced by COP-bleomycin (P = 0.03). Survival of patients with large cell lymphoma treated with CHOP-BCG was better than that observed with CHOP-bleomycin (P = 0.02) or COP-Bleomycin (P = 0.002). Although the explanation for the favorable effect of BCG remains unclear, further clinical trials to evaluate the combination of chemotherapy and other "biologic response modifiers" is warranted for patients with lymphoma.

An investigation of 2'-deoxycoformycin in the treatment of cutaneous T-cell lymphoma.

We have investigated the use of 2'-deoxycoformycin (DCF), a potent inhibitor of adenosine deaminase (ADA), in the treatment of 4 patients with advanced mycosis fungoides (MF). Since DCF has demonstrated an adverse effect in vitro and in vivo on the survival of leukemia T-cell lines, it appeared reasonable to examine its effect in patients with advanced cutaneous T-cell lymphoma. A total of 8 courses of DCF were given to the 4 patients. Since this study was part of an ongoing phase I investigation, each patient received a fixed dose (varying from 4 mg/sq m to 10 mg/sq m daily for 3 consecutive days) on a 28-day schedule. One patient had reversible renal insufficiency. Three patients had reversible myelosuppression. Two patients had a complete remission of disease for 7+ and 9+ mo. respectively. Two additional patients had partial remissions for 4 and 9 mo, respectively. We concluded that effective antitumor activity in advanced MF can be achieved with DCF at doses that may not be associated with prohibitive toxicity. We would encourage further investigation of this agent in patients with advanced cutaneous T-cell lymphoma.

Evidence for the generation of hydroxyl radical during arachidonic acid metabolism by human platelets.

Reactive oxygen species, probably hydroxyl radicals (OH.), have been suggested to be generated during arachidonic acid (AA) metabolism and, once released, these species can modify the rate and extent of various reactions involved in AA metabolism. We have studied this phenomenon in washed human platelets. OH. generation was quantitated using 14C-benzoic acid as a specific trap in a continuous ionization chamber system. Resting platelets did not produce any detectable signal, whereas addition of AA resulted in gradual OH. production with peak values detected at approximately 20 min. Similar studies conducted under nitrogen or after boiling the platelets almost abolished OH. generation. Aspirin had no significant effect, whereas 5,8,11,14-eicosatetraynoic acid decreased the signal by greater than 90%, thus suggesting that OH. is produced primarily through the lipoxygenase pathway. Superoxide dismutase (SOD) and catalase had no effect and, as expected, phenol and mannitol decreased OH. production considerably, by greater than 50% and 90%, respectively. Azide and cyanide also reduced the OH. generation by about two thirds. We conclude that OH. is generated during AA metabolism by human platelets. It is primarily produced via the lipoxygenase pathway and may require a heme-dependent peroxidase. This highly reactive oxidant may play an important role in normal and abnormal hemostasis.

Characteristics of the metabolic response of human monocytes to red cells sensitized with anti-D alloantibodies.

In these studies we have characterized the metabolism of the HMPS pathway of PBMs and PMNs from normal persons during interaction with human red cells sensitized with anti-D alloantibody. This was correlated with ADCC as determined by the 51Cr release assay. In this system, the lysis by PBMs of RBCs sensitized with anti-D alloantibodies was mediated by both monocytes and lymphocytes, although the activity of the monocytes was greater. Monocytes, but not lymphocytes, has a burst in HMPS activity during interaction with anti-D-sensitized RBCs. This could be detected with T:E ratios similar to those which caused 51Cr release from the target. Oxygen was required for optimal lysis of antibody-coated RBCs by monocytes, but ADCC was not totally impaired under hypoxic conditions, suggesting that mononuclear cells may have at least two mechanisms for accomplishing ADCC-one that is oxygen-dependent and another that does not involve oxygen radicals. ADCC under aerobic conditions was accompanied by a burst in HMPS activity. In the absence of oxygen there was a 60% reduction in ADCC and no stimulation of the HMPS. However, results of studies for detection of oxygen radicals using standard scavengers during ADCC were negative. In contrast to monocytes, PMNs did not mediate significant ADCC in similar T:E ratios and did not have a metabolic burst when incubated with anti-D-sensitized RBCs. This appears to relate to the low activity of PMNs compared to monocytes in the lysis of RBCs sensitized with anti-D antibody.

Acquired factor X deficiency with associated defects in platelet aggregation. A response to corticosteroid therapy.

A 79 year old white women presented with a severe bleeding disorder. Evaluation revealed a prothrombin time of 27.6 seconds (control, 11 seconds) and an activated partial thromboplastin time of 61 seconds. Specific clotting factor assays showed an isolated deficiency of factor X ranging from 7 to 12 per cent on three determinations. Platelet aggregation and bleeding time were also abnormal in response to epinephrine and collagen. Factor X levels and platelet aggregation returned to normal and bleeding stopped after institution of corticosteroid therapy.

Probable cure of metastatic testicular tumors treated with sequential therapy.

This clinical trial explores the possibility of inducing long-term unmaintained complete remissions in testicular cancer using sequential multimodality therapy. We designed a prospective study using a combination of vinblastine and bleomycin for three courses followed by cis-dichlorodiammineplatinum(II), actinomycin D, and vincristine until a surgically proven complete remission was achieved. One to three additional consolidation courses were given following surgery, and then all therapy was stopped. Eleven of 15 patients completing therapy have achieved complete remission, with seven patients remaining free of disease without maintenance therapy for 15-36 months (average, > 27 months). We conclude that patients with disseminated nonseminomatous testicular cancer should be treated for cure with intensive primary therapy. Prolonged disease-free status can be achieved without maintenance therapy, and the value of maintenance therapy needs further study.