Hemoglobin Wood beta97(FG4) His replaced by Leu. A new high-oxygen-affinity hemoglobin associated with familial erythrocytosis.

The characterization of hemoglobin Wood (beta97(FG4) His replaced by Leu), a high oxygen affinity hemoglobin with reduced Hill constant is described. The amino acid substitution occurs at the alpha1beta2 interface, in the same position as in hemoglobin Malmö (beta97(FG4) His replaced by Gln) and in an homologous position when compared with hemoglobins Chesapeake (alpha92(FG4) Arg replaced by Leu) and J. Capetown (alpha92(fg4) arg replaced by Gln).

Remission of chronic lymphocytic leukemia after smallpox vaccination.

A 78-year-old man with untreated chronic lymphocytic leukemia (CLL) was revaccinated for smallpox. A severe local reaction and generalized rash followed that responded to treatment with vaccinia immune human globulin. After recovery, the leukocyte count fell to normal and all evidence of CLL disappeared. He remains in complete remission three years after smallpox vaccination.

Ketoconazole in the prevention of candidiasis in patients with cancer. A prospective, randomized, controlled, double-blind study.

A prospective, randomized, controlled, double-blind study was performed between 1982 and 1985 to assess the ability of ketoconazole to prevent fungal infections in selected patients with cancer. Fifty-six patients receiving induction chemotherapy for acute leukemia, autologous bone marrow transplant for refractory nonhematopoietic malignant neoplasms, multidrug chemotherapy for malignant lymphoma, or corticosteroids for brain metastases were randomized to receive either oral ketoconazole, 400 mg/d, or placebo and observed until leukopenia resolved or corticosteroid therapy was stopped. Oral candidiasis developed in eight (28%) of 29 patients receiving placebo compared with none of 27 receiving ketoconazole. However, ketoconazole failed to prevent Candida esophagitis and vulvovaginitis in two patients and one patient, respectively. Furthermore, prophylactic use of ketoconazole did not significantly alter the total number of hospital days, febrile days, or antibiotic days or the requirement for amphotericin B in patients with acute leukemia and autologous bone marrow transplant. Since oral candidiasis can be successfully managed by several different treatment modalities when it does occur, we do not think that the routine prophylactic use of ketoconazole is justified.

Acute myelofibrosis and malignant hypercalcemia.

A 33 year old man presented with symptoms of one week's duration; he had a serum calcium of 22.5 mg/dl and a markedly hypercellular bone marrow. Despite therapy with saline diuresis, furosemide mithramycin, total parathyroidectomy and corticosteroids, symptomatic hypercalcemia was poorly controlled. Inappropriate serum parathyroid hormone (PTH) levels were found before and after parathyroidectomy whereas assays of the peripheral blood for osteoclast-activating factor and prostaglandin E (PGE2) were negative. An elevated leukocyte alkaline phosphate level, the inability to aspirate marrow, the marked generalized hyperplasia of all hematopoietic marrow elements, the focal accumulations of blastic cells and increasing reticulin fiber formation led to the diagnosis of acute myelofibrosis. A single course of cytosine arabinoside and thioguanine therapy was followed by profound hyperphosphatemia, hypocalcemia and death. The rarity of hypercalcemia with myeloproliferative disorders is documented by a review of the world literature, and the possible mechanism for hypercalcemia in this patient is discussed.

Prognostic influence of TNM staging and LDH levels in small cell carcinoma of the lung (SCCL).

To better define the prognostic factors influencing the response to therapy and survival in small cell carcinoma of the lung (SCCL), an expanded "TNM" type staging system was developed and investigated in a series of 73 protocol treated patients. Because serum LDH levels at disease presentation have been correlated to disease extent, response to therapy, and treatment outcome in a number of malignancies, including SCCL, these interrelationships were also analyzed in the protocol patients. The TNM system was found to be a more descriptive and specific "shorthand" for denoting sites of involvement and for indicating the body burden of tumor than the traditional limited-extensive disease (LD-ED) system. A clear statistical advantage could not be shown over the LD-ED system for predicting chemotherapy response or survival, although there were trends suggesting the TNM system could divide patients into three prognostic subgroups. Serum LDH proved to be a useful index of disease extent and therapy outcome. LDH levels at presentation were proportionately higher with more extensive tumor, measured by either the LD-ED or TNM staging. High LDH predicted poorer responses to chemotherapy and lower survival within similar stage subgroups compared to patients with normal LDH levels. The negative effect of elevated LDH was independent of hepatic involvement and did not predict subsequent hepatic failure in any consistent way. The SCCL TNM staging system proposed needs further refinement and should be tested with larger patient numbers. LDH, along with other tumor markers recently identified, need to be integrated into the staging system to form an overall prognostic index.

The role of consolidation irradiation in combined modality therapy of small cell carcinoma of the lung.

Forty-four patients with small cell carcinoma of the lung (SCCL) were treated with a program of combined chemotherapy and radiation therapy. Prophylactic cranial irradiation was given concurrent with the first of six planned cycles of chemotherapy consisting of Cyclophosphamide, Adriamycin, Vincristine and high dose Methotrexate (CAV-M). All patients judged as complete responders (CR) received consolidative thoracic irradiation (CTI) to the locoregional primary lung involvement. The CR rate to chemotherapy alone was 84% for patients with limited disease (LD) and 44% for extensive disease. In comparison to a prior trial, which used similar chemotherapy, but with irradiation withheld until primary site relapse, the actuarial primary site relapse rate at 2 years was reduced by CTI from 92% to 18% (P less than .01). The median primary site remission duration has not yet been reached in the CTI group and was 34 weeks without CTI (P less than .01). CTI increased the 2 year actuarial survival from 6% to 66% (P less than .01) in the chemotherapy CR patients. Median survival has not yet been reached in the CTI group, but was 48 weeks without CTI (P less than .01). Leptomeningeal spinal cord relapse in patients with no prior central nervous system (CNS) involvement occurred in 16% of patients relapsing.

Integration of chemotherapy and radiation therapy for small cell carcinoma of the lung.

Two chemotherapy trials using cyclophosphamide, doxorubicin hydrochloride and high-dose vincristine sulfate with or without methotrexate have induced a 93% incidence of complete remission in limited disease presentation of small cell bronchogenic carcinoma of the lung and 39% incidence in extensive disease. The first trial without consolidation radiotherapy had a local failure rate of 65%, which dropped to 17% with consolidation radiotherapy to the primary and mediastinum. Prophylactic whole brain radiotherapy prevented local recurrence in 98% of evaluable patients. One carcinomatous meningitis and 5 intraspinal recurrences were noted among the 38 patients in the CAV-M trial. We conclude that high-dose vincristine sulfate is associated with an improved incidence of complete remission; that prophylactic whole brain radiotherapy has been highly successful; that prevention of intraspinal recurrence will necessitate the use of craniospinal axis radiation therapy and consolidation radiation therapy improves local control of primary and mediastinum.

The role of thoracic and cranial irradiation for small cell carcinoma of the lung.

Since 1974, 120 previously untreated patients with small cell carcinoma of the lung seen in Therapeutic Radiology at The Medical College of Wisconsin have been entered into one of 4 successive studies. Study I used thoracic irradiation (TI) alone (4500-6000 rad in 3-6 weeks) with chemotherapy at progression. Study II randomized patients with limited disease to TI (3000 rad in 2 weeks) plus either cyclophosphamide, doxorubicin, vincristine (CAV) or total body irradiation (TBI); patients with extensive disease received TI + CAV. Study III employed prophylactic cranial irradiation (PCI) plus CAV and withheld TI unless there was incomplete response or recurrence. Of 93 evaluable patients from the first three studies, 55 had limited and 38 extensive disease. Study I (37 patients) showed a 62% complete response (CR) rate; 43% failed in the chest, 14% had brain metastases, and the median survival was only 22 weeks in spite of a preponderance of limited disease patients. Study II (27 patients) showed a CR of 59%; 30% had brain metastases and the median survival was 48 weeks. Study II patients (29) had a 69% rate; 72% failed in the chest, 4% with PCI developed brain metastases, and the median survival was 50 weeks. In March, 1979, Study IV was initiated; patients receive PCI (2500 rad in 2 weeks) plus high dose CAV, methotrexate and leucovorin. After 6 cycles, consolidation TI (3750 rad in 3 weeks) is given to patients with complete response. Preliminary results with 27 patients treated on this study show a 67% CR rate, a 41% chest failure rate (but only 11% for the patients who received thoracic irradiation) and no intracranial failures, but a 13% extracranial CNS failure rate. PCI, TI and spinal irradiation may be necessary to maximize the probability of long term disease free survival.

Comparison of hemoglobins Wood (alpha 2 beta 2 97 leu) and Malmö (alpha 2 beta 2 97 gln). Diagnostic value of citrate agar electrophoresis.

Diagnostic value of citrate agar electrophoresis. Am J Clin Pathol 71:668-671, 1979. Of approximately three dozen hemoglobin variants that have greater than usual oxygen affinity, nearly half are inseparable from hemoglobin A by electrophoresis at pH 8.6. A comparison of hemoglobins Wood (alpha2beta297leu) and Malmö (alpha2beta297gln) is of interest from several standpoints. They represent similar substitutions at the identical locus in the beta chain. They result in identical clinical and hematologic manifestations. Oxygen affinities of these variants are identical. Both are poorly resolved from hemoglobin A by electrophoresis at pH 8.6. The position of each is identical when studied by isoelectric focusing in polyacrylamide gel. Finally, they are easily distinguished by citrate agar electrophoresis at pH 6.2. The excellent resolution of hemoglobins Malmö and Wood from each other results neither from difference in charge, nor size, nor in quaternary structure. This technic provides a simple but effective means for identifying and differentiating these hemoglobin variants. Comparison with the results of citrate agar electrophoresis of other high oxygen-affinity hemoglobins indicates that the findings for hemoglobins Malmö and Wood are unique and unambiguous.

Late-onset, warfarin-caused necrosis occurring in a patient with infectious mononucleosis.

A 25-year-old man with Klinefelter's syndrome and recurrent thromboplebitis , for which he had been receiving long-term warfarin sodium therapy, had bilateral ecchymoses on the hips coincident with serologically confirmed Epstein-Barr virus-caused mononucleosis. Biopsy specimens taken from the hip lesions showed microscopic findings consistent with a diagnosis of warfarin necrosis. Direct immunofluorescence microscopy disclosed vessel-wall deposition of IgM and heavy upper-dermal deposition of IgG. Electron microscopy disclosed nonspecific endothelial cell blebs that projected into the vessel lumen. The temporal association of mononucleosis with the onset of warfarin necrosis suggests that the viral illness may have precipitated an immunologic endothelial surface reaction, leading to thrombosis and secondary hemorrhage with infarction. To our knowledge, the appearance of warfarin necrosis in a patient receiving long-term, stable anticoagulation therapy has not been previously reported.

Cisplatin and fluorouracil as neoadjuvant therapy in head and neck cancer. A preliminary report.

A randomized, prospective trial utilizing cisplatin and fluorouracil as neoadjuvant chemotherapy in the treatment of advanced squamous cell carcinomas of the upper aerodigestive tract was initiated in January 1983. Sixty patients were stratified by site (oral cavity, 19; larynx, 14; hypopharynx, 14; oropharynx, 11; nasopharynx, one; and paranasal sinuses, one) and by stage (III, 19; IV, 41), and then randomized to receive either standard treatment (defined as preoperative irradiation followed by radical excision or irradiation alone) or adjuvant chemotherapy followed by standard treatment. An additional three patients were entered into the study, but withdrew. Chemotherapy consisted of three cycles for those patients in whom an objective tumor response was observed; nonresponders received standard treatment. Response to chemotherapy was complete in five and partial (greater than 50%) in 18 patients, for an overall response rate of 85%. The follow-up for surviving patients was a minimum of 24 months and a maximum of 44 months. Survival was compared for patients in both treatment groups according to the method of Lee and Desu. Despite excellent tumor response, actuarial survival was 70% in the standard treatment group as opposed to 56% in the experimental group. It was therefore evident that the high response rates reported in previous pilot studies do not necessarily result in improved survival in these cancers.

5-Fluorouracil infusion and low-dose weekly cisplatin: an analysis of increased toxicity.

It has been suggested that the addition of weekly low-dose cisplatin (DDP) may potentiate the efficacy of continuous infusion 5-fluorouracil (5-FU) without adding significant toxicity. To investigate the extent of added toxicity, an analysis of toxicity was completed in 18 patients with advanced cancers treated with continuous ambulatory 5-FU infusion 300 mg/m2/day and weekly low-dose cisplatin (DDP) 20 mg/m2. Ten of the 18 patients (56%) developed multiple (four or more) toxicities during treatment. In addition, toxicity categorized as severe occurred in 10 patients (56%). Seventeen of the 18 patients (94%) required treatment interruption or dose attenuation due to toxicity and most patients experienced a decline in Eastern Cooperative Oncology Group performance status due to treatment-related toxicity. Compared with historical toxicity patterns when 5-FU infusion is administered alone, the addition of DDP has resulted in significant increases in nausea and vomiting, anorexia, diarrhea, stomatitis, and myelosuppression. The addition of low-dose weekly DDP adds significant toxicity and morbidity to the continuous 5-FU infusion regimen.

Multiagent chemotherapy, prophylactic neuraxis irradiation, and consolidative irradiation for small cell carcinoma of the lung.

Between 6/81 and 6/83, 73 patients with small cell carcinoma of the lung were treated according to a prospective protocol in which cyclophosphamide, doxorubicin, and vincristine (CAV) were given concurrently with prophylactic craniocervical irradiation to the level of C5. Both limited and extensive disease patients with normal computed tomography of the brain received 25 Gy in 10 fractions in 2 weeks. Complete responders to CAV received consolidative thoracic irradiation (CTI) to the local-regional primary (37.5 Gy in 15 fractions in 3 weeks), the first 25 Gy in 10 fractions serving as prophylaxis of the C6 to T12 spinal cord. The neuraxis from L1 to S2 then received 25 Gy in 10 fractions in 2 weeks. Consolidative irradiation of localizable metastatic sites was given in extensive disease patients. Partial and nonresponders to CAV received 50-60 Gy in 5-6 weeks to local-regional disease. With a median followup of 29 months, survival was significantly better (p less than .01) in patients receiving CTI to the chest after complete response to CAV (both limited disease and extensive disease) than without CTI. Of 41 patients completing the protocol and without central nervous system (CNS) involvement at presentation, four (9%) failed initially in the CNS (two brain, two spinal axis); CNS failure was the cause of death in all four patients with no other sites of metastases at death in two of these. Failure to complete protocol treatment was due to disease progression during chemotherapy in 25/73 (34%) and chemotherapy related complications (three sepsis, one gastrointestinal bleed) in four of 73 (5.5%) patients. CTI and prophylactic neuraxis irradiation did not increase morbidity or result in mortality in the sequence utilized; prophylactic neuraxis irradiation appears to reduce the CNS relapse rate, and CTI benefits survival.

What is the lowest effective biologic dose for prophylactic cranial irradiation?

Between January 1974 and September 1984, 327 consecutive patients with small cell carcinoma of the lung (SCCL) free of clinical and brain scan (radionuclide or computed tomography) evidence of brain metastasis were treated at the Medical College of Wisconsin Affiliated Hospitals. All patients received single agent chemotherapy, consisting of cyclophosphamide or methotrexate (1974-1975), or combination chemotherapy with cyclophosphamide, doxorubicin, and vincristine with or without methotrexate and leukovorin (1976-1984). Between January 1974 and December 1974, 82 patients were treated with chemotherapy without prophylactic cranial irradiation (PCI). Between 1978 and 1984, all patients received PCI during the first week after diagnosis, simultaneous with their first cycle of chemotherapy. Chest irradiation was given to the complete responders to the chemotherapy. During the first 31/3 years of the study with PCI (January 1978-May 1981), 51 patients received 30 Gray (Gy) in 10 fractions in 2 weeks and five of them (10%) developed brain metastasis. Thereafter, 25 Gy in 10 fractions was consistently administered for PCI. Six of 194 patients (3%) developed brain metastasis. The cumulative (time corrected) probability of brain metastasis was approximately 10% at 1 year and was similar for patients who received 25 Gy and those who received 30 Gy. Although detailed neuropsychological testing has not been performed, clinically apparent late sequelae that might be attributed to PCI have not been seen. Nonetheless, the dose fractionation regimen of 25 Gy in 10 fractions with combination chemotherapy, cyclophosphamide, doxorubicin (or methotrexate), and vincristine is as effective in eliminating subclinical metastasis to the brain. It can be recommended for future trials until more data become available about late sequelae of treatment of SCCL and the patient characteristics and treatment factors that may contribute.

Continuous 5-fluorouracil infusion and alpha interferon in advanced cancers: a report of initial treatment results.

Twenty-four patients with advanced metastatic cancer were treated with continuous intravenous 5-fluorouracil infusion 200-300 mg/m2/day and alpha interferon 3 million units subcutaneously 3 times per week. The average duration of treatment was 87 days (range 22-204 days). 5-fluorouracil could be infused 66% of the planned time on treatment, and patients received an average of 60% of the planned interferon injections. Objective tumor responses were seen in 6 of 17 previously untreated patients (35%). Twenty-two of the 24 patients (92%) experienced toxicity (greater than or equal to ECOG grade II) that required treatment interruption and subsequent dose reduction predominantly for the following reasons: mucositis (67%), hand-foot syndrome (21%), and leukopenia (25%). The incidence of treatment limiting toxicity is higher than previously observed with 5-fluorouracil infusion alone. This suggests true augmentation of 5-fluorouracil effect by interferon. 5-Fluorouracil infusion and alpha interferon is a potentially useful combination that needs further evaluation in future phase II and phase III trials.

Altered immunoregulation in Waldenström's macroglobulinemia. I. The absence of Con A-induced and spontaneous T suppressor cell activity in a patient and his kindred.

In vitro lymphocyte functions in a patient with Waldenström's macroglobulinemia and his kindred were examined. The percentage and number of total peripheral blood T cells and the absolute number of FC gamma bearing T cells were decreased in the patient and family members compared to controls but the B cells and monocytes were normal. In addition, PHA and PWM stimulated proliferation were decreased. Decreased responsiveness to PWM was abrogated by preculturing PBMC in media alone before PWM stimulation. Decreased responsiveness to PHA was not reversed by a similar period of preculture. To further define the above abnormalities in immunoregulation we examined mononuclear subpopulations. In controls, adding purified T cells or Con A activated lymphocytes to autologous cultures which had been stimulated with PHA and PWM significantly decreased proliferative activity. No such suppressive activity of T cells or Con A activated cells from the patient or family members was noted. These data demonstrate an absent or functionally inactive spontaneous and Con A activated T suppressor cells in the family of a patient with Waldenström's macroglobulinemia.

Methemoglobin reduction in red cells: effect of a high oxygen affinity hemoglobin.

Erythrocytes from heterozygous carriers of the high oxygen affinity mutant hemoglobin, Hb Wood, demonstrate lower rates of methemoglobin reduction than normal human red cells when incubated in the in vitro system of Beutler and Baluda. The rate of methemoglobin reduction in red cells from an individual who is heterozygous for both NADH-methoglobin reductase deficiency and Hb Wood shows the combined effects of the two mutations.