Joseph J. Mazza

Full dose versus attenuated dose daunorubicin, cytosine arabinoside, and 6-thioguanine in the treatment of acute nonlymphocytic leukemia in the elderly.

Between July 1, 1981 and November 1, 1982, 45 patients with acute nonlymphocytic leukemia (age, greater than or equal to 70 years) were randomly assigned to receive induction chemotherapy using either daunorubicin, cytosine arabinoside, and 6-thioguanine in full dosage (F DAT) or an attenuated schedule of the same drugs (At DAT) as part of an Eastern Cooperative Oncology Group controlled trial. Forty patients were deemed evaluable, 20 on each arm. The overall complete remission (CR) rate for all patients in both arms was 28% (11/40). There was no significant difference in CR rates between the two arms. There were 12 early deaths (less than 60 days) in the F DAT arm compared with only five early deaths on the At DAT arm (P = .05). Due primarily to this early death rate, the median survival for the F DAT group was 29 days v 159 days for the At DAT groups (P = .02). The range of survival of the patients in CR for the At DAT group given either one or two cycles of induction therapy was 121 to 414 days, while the survival range for the F DAT CR patients was 121-186 + days. The median survival for those not achieving CR was 14 days for the F DAT group v 80 days for the At DAT (P less than .02). Fifty-nine percent of the At DAT patients spent greater than 100 days out of the hospital v 12% for the F DAT group. Attenuated chemotherapy with lower doses of DAT is the preferred induction regimen for elderly patients with acute nonlymphocytic leukemia since it causes fewer early deaths, allows a better quality of life, and yields survival times as durable as intensive therapy.

Comparison of chlorambucil and prednisone versus cyclophosphamide, vincristine, and prednisone as initial treatment for chronic lymphocytic leukemia: long-term follow-up of an Eastern Cooperative Oncology Group randomized clinical trial.

The Eastern Cooperative Oncology Group (ECOG) conducted a study in which patients with advanced chronic lymphocytic leukemia (CLL) were randomized between a regimen consisting of chlorambucil (30 mg/m2 orally day 1) and prednisone (80 mg orally days 1 to 5) (C + P) administered every 2 weeks and a more intensive regimen of cyclosphosphamide (300 mg/m2 orally days 1 to 5), vincristine (1.4 mg/m2 intravenously [IV] day 1), and prednisone (100 mg/m2 orally days 1 to 5) (CVP) given every 3 weeks. Treatment was continued for up to 18 months to maximal response. Of the 122 eligible patients, 60 received C + P, while 62 received CVP. With a median follow-up of 7 years, there were no significant differences in survival (4.8 v 3.9 years, P = .12), complete remission (CR) rate (25% v 23%; P = .83), or duration of response (2.0 v 1.9 years; P = .78) between C + P and CVP. Toxicity was modest despite the prolonged treatment. The long median survival of 4.1 years for stage III and IV patients is superior to that usually reported. This could stem from continuing treatment to maximal response rather than an increase in intensity of therapy. These results are comparable to those reported with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy by other investigators. The data suggest that intermittent C + P administered to maximal response continues to be the standard treatment approach for advanced CLL.

Maintenance chemotherapy prolongs remission duration in adult acute nonlymphocytic leukemia.

The value of maintenance therapy after the achievement of complete remission in adult acute nonlymphocytic leukemia (ANLL) has never been clearly established. A randomized Eastern Cooperative Oncology Group (ECOG) study of postremission therapy compared outcomes in patients who received no further therapy to those administered long-term maintenance chemotherapy. Adverse results in the group administered no further therapy led to early termination of this trial after only 51 patients were randomized. Patients receiving no postremission therapy experienced significantly inferior remission durations (P = .002) compared with patients receiving maintenance therapy. All 26 patients in the group administered no postremission therapy have relapsed, with a median duration of remission of 4.1 months. In contrast, four of 25 patients (16%) who received maintenance therapy remain disease free, with a median duration of remission of 8.1 months.

Virchow’s Contribution to the Understanding of Thrombosis and Cellular Biology

Few physician-scientists have contributed as much to the fundamental understanding of the pathophysiology of cellular biology as Rudolf Virchow. His contribution to the cellular biomedicine paradigm along with the germ theory of Pasteur and Koch formed the basis for many of the medical advances of the twentieth century.1 He was one of the first physicians to examine disease at the cellular level, arguing that the origin of disease was caused by cellular pathology. One area that he studied extensively, and in which he has left lasting contributions to modern medicine, was in the area of thrombosis, specifically venothromboembolism (VTE). For much of the later half of the twentieth century, the so-called Virchow’s Triad has formed the basis for understanding the pathogenesis of VTE and is still widely used to assess VTE risk.2 In order to assess and appreciate the applicability of Virchow’s Triad to current medical practices, it is important first to examine how the principals of Virchow’s original theory of thrombosis continue to be applicable to modern day theory.

Jean-Martin Charcot: The Father of Neurology

To take away from neurology all the discoveries made by Charcot would be to render it unrecognizable. Joseph Babinski Jean-Martin Charcot (figure 1) was born in Paris, France in 1825 at a time when the field of Neurology had not been formally recognized as a distinct specialty. He was a gifted painter who used his artistic abilities and strong visual memory to make associations about patterns of disease in the field of medicine and anatomy. His father, financially limited, decided that the son who performed best amongst the four in school would go on to receive a higher education, a competition that Jean-Martin won, thus providing him the opportunity to enter medical school. Mastery of the French, English, German, and Italian languages enabled him to read the medical literature in these languages, which accounted for his well-rounded knowledge of a variety of subjects including gerontology, diseases of the joints and lungs, and the anatomy, physiology, and pathology of the nervous system.

Phase II trial of 2-chlorodeoxyadenosine in patients with relapsed/refractory acute myeloid leukemia: A study of the Eastern Cooperative Oncology Group (ECOG), E5995

2-Chlorodeoxyadenosine (2-CdA) is a purine analog which has anti-leukemic activity in phase II trials in pediatric acute myeloid leukemia (AML) patients. An adult phase I trial suggested possible similar activity although neurotoxicity at higher doses was seen. We conducted a phase II trial of 2-CdA in patients with relapsed or refractory AML. 2-CdA was administered by continuous intravenous infusion at a dose of 17 mg/m(2) per day x5 days. Patients not achieving aplasia by day 21 were eligible for a second course of therapy. Fifteen patients (nine relapsed and six refractory AML) were enrolled including seven men and eight women with a median age of 60 years and median ECOG PS of 1. There were five deaths on study due to infections (two), AML (two), or hepatic failure (one). The 2-CdA was well tolerated without severe nausea, vomiting or stomatitis (all <grade 2). No severe neurologic complications related to 2-CdA were seen. Grade 4 myelosuppression occurred in nearly all patients with prolonged periods of pancytopenia and BM hypoplasia seen in most. There were no complete responses, though bone marrow aplasia was achieved in eight patients. 2-CdA as a single agent, in the doses used in this study, is ineffective therapy for relapsed or refractory AML.

Multi-drug resistance in chronic lymphocytic leukemia

We evaluated 45 chronic lymphocyte leukemia (CLL) patients for the presence of multi-drug resistance (MDR) by the ex vivo techniques: 1) a functional assay utilizing doxorubicin (dox) retention with modulation; 2) a cytotoxicity assay (MTT) with modulation; 3) and four monoclonal antibodies. Ex vivo tests were correlated with disease stage and prior treatment, and were repeated as patients became resistant to alkylating agents, fludarabine and VAD chemotherapy (infusion of vincristine, dox, and oral dexamethasone). The majority of patients (64.4%) were in early stage and were untreated (62.2%). P-glycoprotein (p-gp 170) was detected most frequently by the monoclonal antibody MRK-16 (48%) and by functional modulation of dox retention by PSC-833 (40.6%) and by functional modulation of the MTT assay with vincristine (0.29) and dox (0.39) with PSC-833 at 1.0 microg/mL. Functional modulation of dox retention with PSC-833 was significantly associated with stage, but not with either the MTT assay or any of the monoclonal antibodies. None of the tests correlated with prior chlorambucil treatment. Correlation of dox retention with the monoclonal antibodies was mild to moderate and became stronger following chlorambucil treatment. Three patients who became resistant to VAD were found to express p-gp 170. We conclude that MDR can frequently be detected in patients with CLL. Furthermore, the expression of p-gp 170 increases with advancing stage, but not prior alkylating agent therapy. The functional expression of p-gp 170 increases with advancing stage and prior treatment and correlates well with monoclonal antibody detection (especially MRK-16). Patients who become resistant to VAD more frequently express p-gp 170 by a variety of techniques. PSC-833 is a more potent modulator of MDR than cyclosporin-A (CsA) ex vivo, and correlates better with stage of disease.

Incidence of Infections in Adult Patients (> 55 Years) with Acute Myeloid Leukemia Treated with Yeast-Derived GM-CSF (Sargramostim): Results of a Double-Blind Prospective Study by the Eastern Cooperative Oncology Group

Between 9/90 and 11/92, the ECOG conducted a double-blind randomized trial of yeast-derived GM-CSF (Sargramostim) versus placebo in 124 patients age > 55–70 with de novo acute myeloid leukemia (AML). Induction therapy consisted of 1–2 courses of daunorubicin (60 mg/m2/day, days 1–3) and cytarabine (100 mg/m2/day, days 1–7). Consolidation therapy consisted of one course of high-dose cytarabine (1.5 g/m2/q12h × 12 doses). GM-CSF (250 μg/m2/day) or placebo was started on day 11 of the first course of induction therapy if the bone marrow on day 10 was hypoplastic and with 500/mm3 and >1,000/mm3 was shorter by an average of 4 and 7 days, respectively in the GM-CSF group (13 versus 17 days and 14 versus 21 days, p ≤ 0.004). Patients given GM-CSF had significantly fewer grade 4, 5 infections (9.6% versus 36.2%, p = 0.002), fewer fatal infections during and within 30 days of completing study drug (5.8% versus 23.4%, p = 0.019), fewer fatal pneumonias (14.3% versus 53.8%, p = 0.046) among subjects who contracted a pneumonia, and fewer deaths associated with a fungal infection (1.9% versus 19.1%, p = 0.006). Fewer patients given GM-CSF died in the first 180 days of entry onto study (17.3% versus 42.6%, p = 0.008). There were no increase in the frequency of resistant or recurrent leukemia and in the incidence of adverse events ascribed to GM-CSF. In conclusion, GM-CSF is safe and effective in older patients undergoing induction therapy for AML and it significantly ameliorates infection rates and complications of infections. Its role in younger patients or in patients with recurrent disease needs to be investigated.

Josef Brudzinski and Vladimir Mikhailovich Kernig: Signs for Diagnosing Meningitis

Inflammation of the meninges, or meningitis, is a serious neurological insult that involves the membranes (dura, pia and arachnoid matter) covering the brain and spinal cord. Meningitis may be caused by any of a host of infectious and non-infectious agents including bacteria, viruses, fungi, parasites, drugs, autoimmune disorders, or malignancy which considerably influences morbidity and mortality.1 Currently, the case-fatality rate for adults with bacterial meningitis is approximately 25% with temporary or permanent neurologic sequelae occurring in 21% to 28% of survivors.2,3 These rates are slightly lower for children older than 1 month, but remain significant, and early diagnosis is critical in improving outcomes.4,5 Symptoms of acute meningitis include high fevers, chills, joint pain, decreased mental status, headache (“worst headache of my life”), stiff neck, photophobia, and rash. Early indicators such as rash or joint pain may present abruptly depending on the etiologic agent. One study reported that initial symptoms appear on average 24 hours prior to hospital admission.6 A major predictor of outcome in patients diagnosed with bacterial meningitis is the time that has elapsed from the onset of symptoms to the initiation of antibiotic treatment.2,7,8 Empiric treatment with selected antibiotics is based on age of the patient and associated co-morbidities. Critical and timely diagnosis may be facilitated by Kernig’s and Brudzinski’s signs. These two eponyms are commonly associated with meningitis.

Adolf Kussmaul: distinguished clinician and medical pioneer.

Increased jugular venous pressure with inspiration is commonly referred to as Kussmaul’s sign; and the disappearance of the radial pulse or a drop in systolic blood pressure of 10 mmHg or greater with inspiration is recognized as pulsus paradoxus. Both Kussmaul’s sign and pulsus paradoxus are commonly attributed to the discoveries of Dr. Adolf Kussmaul. Together these two clinical signs are important assessors of pericardial or mediastinal disease (table 1 ▶). Table 1. Signs commonly associated with Kussmaul. On February 22, 1822, Adolf Kussmaul (figure 1 ▶) was born in the farming community of Graben, Germany.1 Exposed to medicine at an early age, he accompanied his father, a physician, on house calls and autopsies. At the age of 18, Kussmaul began studying medicine at the University of Heidelberg where he received his doctorate of medicine.2 After graduation in 1845, the University of Heidelberg appointed Dr. Kussmaul to Professor of Medicine.3 His intellectual curiosity led him to study and write about many topics including aphasia, ophthalmologic anatomy, gastric lavage, obstetrics, and polyarteritis nodosa.2 Among his numerous contributions to the medical field, Kussmaul’s sign is considered one of his more significant discoveries and is still used today by astute clinicians, providing important information that frequently helps in directing further investigation. Figure 1. Adolf Kussmaul (1822–1902). Photo courtesy of the US National Library of Medicine.