Thomas P. Duffy

Serial Assessment of Doxorubicin Cardiotoxicity with Quantitative Radionuclide Angiocardiography

We measured cardiac performance sequentially, using quantitative radionuclide angiocardiography to estimate left ventricular ejection fraction in 55 patients receiving doxorubicin for treatment of cancer. With final doxorubicin dosages greater than 350 mg per square meter, the lowest ejection fraction measured was significantly less than the initial determination. Five patients had severe cardiotoxicity (congestive heart failure). All had an ejection fraction of less than 30 per cent at the time of heart failure, and demonstrated moderate cardiotoxicity (a decline in ejection fraction by at least 15 per cent to a final value of less than 45 per cent) before clinical manifestations. Six patients with moderate toxicity in whom doxorubicin was discontinued did not have heart failure or a further decline in ejection fraction during the follow-up period. Moderate toxicity was continued, but mild toxicity (decline of ejection fraction by greater than 10 per cent, noted in 11 patients) was not well predicted. The assessment of radionuclide left ventricular ejection fraction during doxorubicin therapy may make it possible to avoid congestive heart failure.

The mast cell and mast cell disease

Mast cell disease or mastocytosis is a heterogeneous group of clinical disorders characterized by the proliferation and accumulation of mast cells in a variety of tissues, most often the skin. The signs and symptoms of mast cell disease are varied, dependent on the localization of mast cells in different organs and the local and systemic effects of mediators released from these cells. Although mast cell disease is most commonly identified in the skin, involvement of the skeletal, hematopoietic, gastrointestinal, cardiopulmonary, and central nervous systems may be seen. Clinical management of mastocytosis depends most heavily on knowledge of the diverse effects of mast cell mediators on various tissues and organs, the stimuli that can cause their release, and the different methods available for blocking the effects of these mediators.

Pulmonary hypertension in type 1 Gaucher’s disease: genetic and epigenetic determinants of phenotype and response to therapy☆

Type 1 Gauchers disease (GD) is recognized for striking but unexplained phenotypic diversity. Rarely, severe pulmonary hypertension (PH) may occur in GD but its clinical spectrum, determinants or its response to enzyme replacement therapy (ERT)+/-vasodilators is not known. One hundred and thirty-four consecutive patients with Type 1 GD were screened to estimate right ventricular systolic pressure (RVSP) by Doppler echocardiography. Ninety-four patients were on ERT and 40 were untreated. Eight additional GD patients were studied that represented consecutive tertiary referrals with severe PH. Angiotensin converting enzyme (ACE) gene polymorphisms and acid beta-glucosidase gene (GBA) mutations were determined by DNA analysis. Mild, asymptomatic PH (RVSP>35<50 mmHg) was prevalent in Type 1 GD: 30% in untreated patients and 7.4% among patients receiving ERT (P<0.001). Splenectomy was strongly associated with severe, life-threatening PH: all patients with severe PH (RVSP 50-130 mmHg) were asplenic compared to only 31% of patients with RVSP<50 mmHg (Odds ratio [OR] 28.8, 95% CI 1.6-531.6, P<0.001). Other characteristics of patients presenting with severe PH were poor compliance to ERT (4/9 patients) or no ERT (5/9 patients), a family history of a sib with GD and PH (2/2 patients), an excess of ACE I allele (OR 2.3, 95% CI 1.1-4.9, P=0.034) and an excess of non-N370S GBA mutation (OR 6.0, 95% CI 1.1-33, P=0.003). Severe PH was ameliorated by ERT+/-vasodilators during 4.6+/-4.0 yr (range 1-12 yr) follow-up; three patients were initially considered for lung transplantation but improved such that they are no longer active transplant candidates. Our study reveals a remarkable predisposition for PH in type 1 GD. Progression to severe, life-threatening PH occurs in the presence of additional genetic factors (non-N370S GBA mutation, positive family history, and ACE I gene polymorphism) and epigenetic modifiers (i.e., asplenia and female sex). Splenectomy should be avoided and in high-risk patients, ERT+/-vasodilators/coumadin should be initiated.

Acute fatty liver of pregnancy: a reassessment based on observations in nine patients

Acute fatty liver of pregnancy was diagnosed in nine patients over a 10-year period. Eight patients had severe hepatic dysfunction typical for this syndrome and one had subclinical disease but typical hepatic histologic findings. All patients survived with little fetal wastage; all had preeclampsia. Histologic findings included cholestasis, hepatocellular necrosis, and inflammation, as well as microvesicular fat. Histologic findings from biopsy specimens of four of seven patients were initially misinterpreted as hepatitis. This disorder may have both a broad clinical and histologic spectrum; it is probably not rare but often misdiagnosed, perhaps as viral hepatitis. The concurrence of this disorder with toxemia of pregnancy suggests that these entities may be pathophysiologically related.

A Clinician's Approach to Clinical Ethical Reasoning

We offer a systematic strategy that situates clinical ethical reasoning within the paradigm of clinical reasoning. The trajectory of this strategy parallels clinical reasoning: a plain statement of the initial problem, careful gathering of data, a differential diagnostic assessment, and articulation and confirmation of a justified plan. This approach pays special attention to the goals of medical care, because so much depends on whether or not physician and patient share the same goals. This approach also addresses the heterogeneity of clinical problems that at first appear ethical and acknowledges the ethical pluralism that pervades clinical ethics.

Flare in Neuropathy Following Rituximab Therapy for Waldenstrom's Macroglobulinemia

TO THE EDITOR: Waldenstrom’s macroglobulinemia is a lowgrade lymphoma characterized by a serum monoclonal immunoglobin M (IgM) protein spike and monoclonal lymphoplasmacytic cells present in the bone marrow. Approximately 5% to 10% of patients develop peripheral neuropathy, which may be immune-mediated as a result of paraprotein directed against myelin-associated glycoprotein (anti-MAG) or glycolipids. Therapy is challenging, with some success reported with steroids, chemotherapy, intravenous immunoglobin (IVIg), or plasma exchange. Recently, the monoclonal anti-CD20 antibody, rituximab, has been used, sometimes in combination with chemotherapy, with improvement in more than 80% of treated pa

Disseminated intravascular coagulation and excessive fibrinolysis in a patient with metastatic prostate cancer : response to Epsilon-aminocaproic acid

Background. Disseminated intravascular coagulation (DIC) and primary fibrinolysis have both been reported in association with prostate carcinoma. The correct diagnosis of the coagulopathy can be difficult and the appropriate management controversial.

Internists’ attitudes towards terminal sedation in end of life care

Objective: To describe the frequency of support for terminal sedation among internists, determine whether support for terminal sedation is accompanied by support for physician assisted suicide (PAS), and explore characteristics of internists who support terminal sedation but not assisted suicide. Design: A statewide, anonymous postal survey. Setting: Connecticut, USA. Participants: 677 Connecticut members of the American College of Physicians. Measurements: Attitudes toward terminal sedation and assisted suicide; experience providing primary care to terminally ill patients; demographic and religious characteristics. Results: 78% of respondents believed that if a terminally ill patient has intractable pain despite aggressive analgesia, it is ethically appropriate to provide terminal sedation (diminish consciousness to halt the experience of pain). Of those who favoured terminal sedation, 38% also agreed that PAS is ethically appropriate in some circumstances. Along a three point spectrum of aggressiveness in end of life care, the plurality of respondents (47%) were in the middle, agreeing with terminal sedation but not with PAS. Compared with respondents who were less aggressive or more aggressive, physicians in this middle group were more likely to report having more experience providing primary care to terminally ill patients (p = 0.02) and attending religious services more frequently (p<0.001). Conclusions: Support for terminal sedation was widespread in this population of physicians, and most who agreed with terminal sedation did not support PAS. Most internists who support aggressive palliation appear likely to draw an ethical line between terminal sedation and assisted suicide.

Development of leukemia after doxorubicin and cisplatin treatment for ovarian cancer

Alkylating agents have been the major group of chemotherapeutic agents associated with an increased incidence of secondary leukemias. In ovarian cancer alkylating agents have resulted in a lesser, although still increased, risk of secondary malignancies. This paper reports two cases of ovarian cancer treated with cisplatin and doxorubicin (Adriamycin, Adria Laboratories, Columbus, OH), and the subsequent development of an acute nonlymphocytic leukemia and a preleukemia syndrome. This regimen does not contain alkylating agents, and has not been associated with leukemia in patients with ovarian cancer. In these two cases, abnormalities of chromosomes 5, 7, 11, and 17 are reported which have been shown to occur in therapy‐related leukemia. Cancer 64:2459–2461, 1989.

Sickle myonecrosis revisited

This review focuses on the classification of sickle myonecrosis in the context of sickle cell vaso-occlusive crisis. Further, the potential and novel use of magnetic resonance imaging to further clarify the nature of sickle crisis is discussed.