Perspectives on care at the close of life. Management of dyspnea in patients with far-advanced lung disease: "once I lose it, it's kind of hard to catch it... ".

Dyspnea is a common problem among patients with interstitial fibrosis, lung cancer, cystic fibrosis, and chronic obstructive pulmonary disease. The slow but steady progression of such diseases, often punctuated by acute exacerbations or secondary illnesses, can lead to decision-making dilemmas among patients and their caregivers, such as when to accept mechanical ventilation, when to forgoe aggressive therapies, and when to make formal end-of-life care plans. Two cases, a 74-year-old woman with dyspnea secondary to emphysema and a 65-year-old woman with recurrent lung cancer and severe exertional fatigue and dyspnea, illustrate how dyspneic patients approaching the end of life can be evaluated and treated. Four management strategies for dyspnea are discussed: reducing ventilatory impedance, reducing ventilatory demand, improving respiratory muscle function, and altering central perception. Physicians should encourage end-stage lung disease patients and their families to discuss issues such as hospitalization and mechanical ventilation, to prepare advance directives, and to participate in a plan to manage their dyspnea.

The natural history and molecular heterogeneity of HIV-associated primary malignant lymphomatous effusions.

Primary malignant lymphomatous effusions arising in individuals infected with the human immunodeficiency virus, type 1 (HIV-1) represent a rare subset of HIV-associated lymphomas. Previous studies have demonstrated that the malignant cells are monoclonal (as defined by rearrangement of the immunoglobulin gene), express cell surface CD38, and are infected with Epstein-Barr virus (EBV) and human herpes virus, type 8 (HHV-8). Despite these detailed molecular and immunophenotypic studies, clinical information on this disease entity is scant, prompting us to review the clinical features of eight cases seen at our institutions. All eight patients had total peripheral CD4+ lymphocytes < 200/microliter and presented with complaints related to body cavity distension. Routine laboratory values were nondiagnostic and yielded no prognostic information. Only two patients could tolerate and thus received chemotherapy with no obvious impact on their clinical course. The mean overall survival after diagnosis was 60 days (range 6-166 days). Four patients were examined at autopsy. The primary malignant lymphomatous effusion either was the immediate cause of death or contributed significantly to the death of only two. All four patients examined post mortem, however, had lymphomatous infiltration of serosal surfaces adjacent to the site of the primary malignant effusion. Molecular and immunologic studies performed on the malignant cells and effusion fluids revealed universal expression of cell surface CD38 and the presence of HHV-8 gene sequences, but in contrast with previous studies, only four had rearranged immunoglobulin genes or EBV present: IL-6 and IL-10 levels in the malignant effusion fluids were markedly elevated. In summary, this rare subset of HIV-associated lymphomas in our eight patients arose late in the course of HIV-associated disease, had a rapid clinical course, and was molecularly heterogeneous. A pathogenetic role for HHV-8 alone in this disease process is strengthened by our observation of four cases lacking EBV but containing HHV-8.

Physician responses to a hospital policy allowing them to not offer cardiopulmonary resuscitation.

OBJECTIVE: To determine whether physicians followed a hospital policy permitting them to not offer cardiopulmonary resuscitation (CPR) to patients considered unlikely to benefit from this therapy. DESIGN: Prospective series. SETTING: San Francisco General Hospital, a university-affiliated public hospital. PATIENTS: Attending physicians were interviewed about patients admitted over a period of 5 consecutive months for whom do-not resuscitate (DNR) orders were written. Only the first patient for whom each physician wrote a DNR order was included. MAIN OUTCOME MEASURES: Responses of physicians to questions regarding their initiation of DNR orders for these patients. RESULTS: Sixty-nine physicians responded to questions about DNR orders written for 69 patients. Fifty-seven of these physicians said that they were aware of the hospital policy, and 49 of the 57 physicians said that they generally agreed with it. Thirty-three physicians felt that CPR should be offered only to patients likely to benefit from it. In contrast, 36 physicians said that CPR should be offered to all patients, regardless of benefit. CPR was offered to 41 patients and 15 surrogates; 27 of these patients were considered to be unlikely to benefit from CPR. CONCLUSION: Despite a policy that allows them to do otherwise, physicians usually offered CPR to patients, regardless of benefit. Most physicians believed that CPR should be offered to all patients. These findings suggest that policies such as that of San Francisco General Hospital may not be compelling because physicians hold attitudes that are inconsistent with the policies.

Phase I trial of a 5-day infusion of L-leucovorin plus daily bolus 5-fluorouracil in patients with advanced gastrointestinal malignancies.

The combination of leucovorin [(6d,l)-5-formyl-tetrahydrofolate] and 5-fluorouracil (5-FU) has increased efficacy compared to 5-FU alone as treatment of advanced colorectal cancer. Leucovorin is metabolized to methylene tetrahydrofolate, which potentiates the antitumor actions of 5-FU by forming a ternary complex of thymidylate synthase, fluorodeoxyuridine and methylene tetrahydrofolate. Only l-leucovorin is metabolized to methylene tetrahydrofolate and forms this ternary complex. However, d-leucovorin may not be inert. d-Leucovorin may impair cellular uptake and metabolism of l-leucovorin, thereby inhibiting the actions of l-leucovorin. Because of this possible limitation to the effectiveness of racemic leucovorin, we have begun to explore the effects of the pure, biologically active isomer, l-leucovorin. In this phase I trial, patients with advanced gastrointestinal malignancies were treated with a 5-day continuous infusion of l-leucovorin and daily intravenous boluses of 5-FU at 370 mg/m2. The dose of l-leucovorin was escalated in groups of three patients at four doses, 200 mg/m2 per day, 400 mg/m2 per day, 700 mg/m2 per day and 1000 mg/m2 per day. Treatment was repeated every 28 days. Seventeen patients with advanced gastrointestinal cancers entered the trial. Sixteen patients were evaluable for toxicity. Toxicity was similar to that expected for leucovorin plus 5-FU. The most common severe toxicities (and the number of patents affected) were: diarrhea (2), mucositis (2), nausea/vomiting (1), and abdominal/rectal pain (2). The maximum tolerated dose of l-leucovorin was 700 mg/m2 per day. Twelve patients were evaluable for response. One complete, one partial and one minor response were observed. All responses occurred among the nine patients with colorectal carcinomas. The combination of l-leucovorin and 5-FU is well tolerated by patients and appears active for treatment of advanced colorectal carcinomas. Additional clinical trials are necessary to determine if l-leucovorin is more effective than d,l-leucovorin for modulating the effectiveness of 5-FU.

Independent recombination between avian leukosis virus terminal sequences and host DNA in virus-induced proliferative disease.

A cDNA transcript of Rous sarcoma virus, which contained the long terminal repeat (LTR) and some additional 3'-terminal sequences, was inserted into the plasmid pBR322. This recombinant plasmid, p53, was then used as a hybridization probe to detect viral terminal sequences in DNA from a number of tissues of birds with a variety of avian leukosis virus (ALV)-induced proliferative diseases. Using restriction endonuclease digestion and blot hybridization analysis, we detected, in addition to standard ALV genomes, viral terminal sequences linked to host DNA and not to viral genes. In DNA from bursal lymphomas and nephroblastomas, we observed small numbers of integration sites occupied by sequences in p53 and lacking most or all of the remainder of the viral genome. In DNA from osteopetrosis, we observed apparently multiple copies of molecules containing host DNA linked to viral LTR sequences. Some of these structures were contained in discrete, probably unintegrated, DNA molecules. We concluded that viral LTR sequences can be inserted as independent elements during recombination with host DNA in some forms of interaction between exogenous retroviruses and host cells. Because the LTRs have been implicated in integration and transcription of viral genes, the possibility that translocation or activation, or both, of host genes may occur as a consequence of viral infection is reinforced by these observations.