A phase I trial of pan-Bcl-2 antagonist obatoclax administered as a 3-h or a 24-h infusion in combination with carboplatin and etoposide in patients with extensive-stage small cell lung cancer.

BACKGROUND: Bcl-2 family genes are frequently amplified in small cell lung cancer (SCLC). A phase I trial was conducted to evaluate the safety of obatoclax, a Bcl-2 family inhibitor, given in combination with standard chemotherapy. METHODS: Eligible patients (3-6 per cohort) had extensive-stage SCLC, measurable disease, ≤ 1 before therapy, Eastern Cooperative Oncology Group performance status 0 or 1, and adequate organ function. Patients were treated with escalating doses of obatoclax, either as a 3- or 24-h infusion, on days 1-3 of a 21-day cycle, in combination with carboplatin (area under the curve 5, day 1 only) and etoposide (100 mg m(-2), days 1-3). The primary endpoint was to determine the maximum tolerated dose of obatoclax. RESULTS: Twenty-five patients (56% male; median age 66 years) were enrolled in three dose cohorts for each schedule. Maximum tolerated dose was established with the 3-h infusion at 30 mg per day and was not reached with the 24-h infusion. Compared with the 24-h cohorts, the 3-h cohorts had higher incidence of central nervous system (CNS) adverse events (AEs); dose-limiting toxicities were somnolence, euphoria, and disorientation. These CNS AEs were transient, resolving shortly after the end of infusion, and without sequelae. The response rate was 81% in the 3-h and 44% in the 24-h infusion cohorts. CONCLUSION: Although associated with a higher incidence of transient CNS AEs than the 24-h infusion, 3-h obatoclax infusion combined with carboplatin-etoposide was generally well tolerated at doses of 30 mg per day. Though patient numbers were small, there was a suggestion of improved efficacy in the 3-h infusion group. Obatoclax 30 mg infused intravenously over 3 h on 3 consecutive days will be utilised in future SCLC studies.

Carcinoma of unknown primary site: treatment with 1-hour paclitaxel, carboplatin, and extended-schedule etoposide.

PURPOSE: To evaluate the efficacy and toxicity of a novel chemotherapy combination that includes paclitaxel, carboplatin, and extended-schedule etoposide in the treatment of patients with carcinoma of unknown primary tumor site. PATIENTS AND METHODS: Fifty-five patients with carcinoma of unknown primary tumor site were treated with the following regimen, administered every 21 days: paclitaxel 200 mg/m2 by 1-hour intravenous (I.V.) infusion on day 1, carboplatin at an estimated area under the concentration-time curve (AUC) of 6.0 on day 1, and etoposide 50 mg alternated with 100 mg orally on days 1 through 10. Responding patients received a total of four courses of treatment. The following histologies were included: adenocarcinoma, 30 patients; poorly differentiated carcinoma (PDC) or poorly differentiated adenocarcinoma (PDA), 21; poorly differentiated neuroendocrine carcinoma, three; and squamous carcinoma, one. RESULTS: Twenty-five of 53 assessable patients (47%; 95% confidence interval [CI], 33% to 61%) had major objective responses to treatment (seven complete responses). Response rates were similar in patients with adenocarcinoma versus PDC (45% and 48%, respectively). The actuarial median survival time for the entire group was 13.4 months. The regimen was well tolerated, with only seven hospitalizations for treatment of neutropenia and fever (4% of courses) and no treatment-related deaths. CONCLUSION: The combination of paclitaxel, carboplatin, and extended-schedule etoposide is highly active and well tolerated in patients with carcinoma of unknown primary tumor site. Response rates and survival in this multicenter community-based trial compare favorably with all previously studied empiric regimens. In addition, this regimen is substantially less toxic and easier to administer than the cisplatin-based regimens previously used in this setting. If this level of efficacy is confirmed, this treatment should be considered standard first-line therapy in patients with carcinoma of unknown primary tumor site.

Field use of hair epilation force in nutrition status assessment.

The nutritional status of 69 Nigerians, age 1 month to 75 yr was assessed with the Krumdieck trichotillometer, which measures the force required to epilate a hair (epilation force, EF). EF of normal subjects (serum albumin greater than or equal to 3.5 g/dl) was 36.5 +/- 9.5 mg (mean +/- SD)). EF was significantly lower (25.7 +/- 10.6 g) in malnourished subjects (serum albumin less than or equal to 3.0 g/dl). EF correlated significantly with weight-for-height, mid-arm circumference, mid-arm muscle circumference, and serum albumin (r = 0.36, 0.32, 0.30, and 0.30, respectively, (p less than 0.05), but did not correlate significantly with triceps skinfold. These findings are in agreement with the clinical impression that hair pluckability is affected more by protein depletion than by energy depletion. The trichotillometer may be a useful tool in assessment of protein nutritional status in the field since it requires little training, and no laboratory.

EEG in dialysis encephalopathy.

Electroencephalography (EEG) in dialysis encephalopathy (DE) was investigated by collecting 173 EEGs from 77 dialyzed patients; 26 had DE. An attempt was made to predict the DE patients, as opposed to the control group without DE, on the basis of EEG alone. Based on the presence or absence of bilateral spike and wave complexes, 91% of the patients along with 91% of their EEGs were correctly placed into the proper clinical category. Also, diffuse slow waves, usually seen in bursts maximal on the frontal areas, appeared in the DE group significantly more often and also with a greater degree of abnormality than in the non-DE group. Considerable variability was noted in the EEGs of these patients. The bilateral spike and wave complexes were discused as an EEG marker of dialysis encephalopathy, which now seems to be related etiologically to aluminum toxicity.

An acute myeloproliferative disorder characterized by myelofibrosis and blast cells that express phenotypic properties associated with multiple hematopoietic lineages.

The authors investigated the blast cells obtained from two patients with acute myelofibrosis with the use of recently developed immunochemical and ultrastructural markers. They intended to examine the expression of megakaryoblastic, erythroblastic, myeloblastic, and monoblastic properties in these cells. Respectively, 20% and 15% of the blasts from patient 1 and patient 2 expressed a megakaryoblastic phenotype as determined by reactivity with a polyclonal platelet glycoprotein antisera (PGP). However, 55% and 73% of these patients' blasts also exhibited myeloid/monocytic properties. Ultrastructural studies clearly demonstrated findings consistent with the presence of myeloblasts, monoblasts, and erythroblasts, as well as undifferentiated agranular blasts. These findings demonstrate the existence of a disorder in which blast cells simultaneously express properties associated with multiple hematopoietic lineages. This disorder is characterized by impaired terminal differentiation.

Successful treatment of thrombotic thrombocytopenia purpura by vincristine.

Two patients with thrombotic thrombocytopenia purpura (TTP) are described in whom vincristine administration appeared to play a role in successful outcomes. The first patient with chronic TTP responded partially to plasma exchange followed by plasma infusion and transiently to splenectomy, but developed a complete long lasting remission after a single injection of intravenous vincristine. The second patient developed a complete remission following vincristine administration and plasma exchange. Although vincristine's mechanism of action in TTP is obscure, we suggest that vincristine is effective in the treatment of this infrequent and often fatal disease.

G6PD Huntsville: a new glucose-6-phosphate dehydrogenase associated with chronic hemolytic anemia.

We describe a previously unreported glucose-6-phosphate dehydrogenase (G6PD) variant. G6PD Huntsville was found in a Caucasian male, resident of Huntsville, Alabama who was investigated for otherwise unexplained chronic hemolytic anemia. An unusual feature of this unique, apparently hemolytic, G6PD mutant is that its red cell enzymatic activity has not been decreased. The mutant enzyme is unstable. Additionally, the enzyme variant is characterized by normal electrophoretic mobility, biphasic and slightly alkaline pH optimum, and abnormal kinetics for the natural substrates G6PD and NADP as well as the artificial substrates deamino NADP. Its activity for another artificial substrate 2-deoxy G6PD is normal. The inhibition constant for NADPH is normal. The subject has had no evidence of episodic jaundice.

Mucormycosis: a community hospital perspective.

Mucormycosis (synonymous with phycomycosis and zygomycosis) is a devastating fungal infection which usually involves patients with diabetes mellitus, often complicated by ketoacidosis, and malignant neoplasms, commonly leukemia and lymphoma. Clinical manifestations include rhinocerebral, pulmonary, disseminated, isolated cerebral, gastrointestinal and cutaneous disease. Common to all forms of mucormycosis is vascular invasion with production of necrotic tissue. The diagnosis is achieved by demonstrating broad, non-septate hyphae with right-angle branching in a tissue biopsy specimen. Successful treatment consists of early diagnosis, intensive systemic antifungal therapy with amphotericin B, aggressive surgical debridement and control of the underlying disease. In our experience with mucormycosis at Huntsville Hospital, the patients were immuno- compromised and the infection was restricted to the lung. Despite use of amphotericin B in all patients, the only one who survived underwent surgical section of infected tissue.

Dialysis encephalopathy and aluminum exposure: an epidemiologic analysis.

We identified 55 patients with dialysis encephalopathy in six dialysis centers studied by means of a uniform clinical classification. Dialysis encephalopathy was the direct cause of death in most cases, and the disease appeared to significantly shorten survival. The overall attack rate of dialysis encephalopathy was 4% and varied among dialysis centers from 2.2% to 14.7%. In two centers with adequate data, the attack rate for dialysis encephalopathy rose significantly with increasing cumulative aluminum exposure via dialysate, and the mean cumulative aluminum exposure for patients with the disease was significantly higher than that for all other patients at risk. We further demonstrated that the cumulative level of aluminum tolerated by the patient before onset of symptoms was inversely related to the average aluminum concentration of dialysate water.

Multiple buoyant densities of hepatitis A virus in cesium chloride gradients.

Hepatitis A virus (HAV) recovered from stools of human cases of hepatitis A and from stools of chimpanzees experimentally infected with HAV was shown to possess multiple buoyant densities in CsCl gradients. The greatest proportion of HAV was most frequently found at a buoyant density of 1.32-1.34 g/cm3, however, large proportions of HAV were also frequently found at higher densities, including 1.36-1.37, 1.40-1.42, and 1.45-1.48 g/cm3. These findings are consistent with the notion that HAV may be a parvovirus.

Serological testing for hepatitis B in male homosexuals: special emphasis on hepatitis B e antigen and antibody by radioimmunoassay.

Serological markers for hepatitis B virus in male homosexuals demonstrated a high prevalence of past and present infection. Seropositivity of 91% for hepatitis B e antigen or antibody was demonstrated by radioimmunoassay in hepatitis B surface antigen-positive specimens.

Hepatitis B testing in the families and villages of five young eskimos with primary hepatocellular carcinoma.

A 15-year-old female Eskimo and a 22-year-old male Eskimo from a southwestern Alaskan village (population 540) were diagnosed as having primary hepatocellular carcinoma (PHC) in December, 1977. The fathers of both patients also died of PHC. Three additional cases of PHC affecting young Alaskan Eskimos had been diagnosed since 1972, all from neighboring villages. Four of the five young patients were positive for hepatitis B surface antigen (HBsAg), and the family members of three patients were all positive for HBsAg or antibody to this antigen (anti-HBs). The other two families had no members positive for HBsAg. The prevalence of HBsAg in the villages of these patients ranged from 0--5%, and the prevalence of anti-HBs ranged from 3--25%. This part of Alaska has a high rate of infection with hepatitis B virus and an increased incidence of PHC. However, other Alaskan villages of similar ethnic background have considerably higher rates of hepatitis B infection than the four villages described and to date they have no PHC. This suggests that genetic and/or environmental factors in addition to hepatitis B infection may have a role in the etiology of PHC in Alaska.

Delayed development of antibody to hepatitis B surface antigen after symptomatic infection with hepatitis B virus.

During a 2-year period, 38 patients with clinical hepatitis B virus infection were seen at the Public Health Service Alaska Native Hospital in Bethel. This hospital serves an area in southwest Alaska that is hyperendemic for hepatitis B virus. The patients came to the hospital at various times from 15 scattered villages, and 92% were Eskimo. None of the patients had a recent history of hypodermic injection or blood transfusions. Twenty-five patients, all originally positive for hepatitis B surface antigen (HBsAg), were followed for up to 5 years after onset of illness, and 15 were either slow to develop, or never developed, antibody to HBsAg (anti-HBs), although only one patient became a chronic carrier of HBsAg. Six patients had a prolonged "window phase" between the disappearance of HBsAg and the appearance of anti-HBs which lasted for more than 1 year. Three patients had only transient anti-HBs after HBsAg disappeared, and five never developed measurable anti-HBs at all. All patients had antibody to hepatitis B core when both HBsAg and anti-HBs were absent. In contrast to studies in other populations, only 42% had anti-HBs 1 year after onset of illness, 63% had it at 18 months, 70% had it at 2 years, and 80% had it at 5 years. Factors related to ethnicity might account for the differences in the development of anti-HBs after acute symptomatic hepatitis B virus infection seen in Eskimos when compared with whites.

Carcinoma of unknown primary site.

BACKGROUND: The long term survival and toxicity associated with the chemotherapy combination of paclitaxel, carboplatin, and extended-schedule etoposide used for the treatment of patients with metastatic carcinoma of unknown primary site were evaluated. METHODS: Seventy-one patients were treated between March 1995 and November 1996 with paclitaxel, carboplatin, and oral etoposide every 21 days. Stable or responding patients received four to eight courses of therapy. The following histologies were represented: well differentiated adenocarcinoma (34 patients); poorly differentiated adenocarcinoma or poorly differentiated carcinoma (30 patients); poorly differentiated neuroendocrine carcinoma (6 patients); and squamous cell carcinoma (1 patient). RESULTS: Forty-eight percent of assessable patients had major responses to therapy (95% confidence interval, 39%-55%), and 10 patients (15%) had complete responses. There were no response differences among the major histologic types. The median survival for all 71 patients was 11 months, and the 1-year, 2-year, and 3-year survival rates were 48%, 20%, and 14%, respectively. The minimum follow-up period was 34 months (range, 34-50 mos). The regimen was tolerated well with no treatment-related deaths and only 12 hospitalizations for neutropenia and fever. There was no serious long term toxicity. CONCLUSIONS: In this large Phase II trial, the combination of paclitaxel, carboplatin, and oral etoposide produced major responses or stable disease status in nearly 80% of patients who had carcinoma of unknown primary site. The median survival and 1-year, 2-year, and 3-year survival rates were noteworthy. The current study obtained similar or superior results to those seen with chemotherapy for many other groups of patients, such as those who had well defined advanced malignancies, those who were considered to have responsive tumors, and those who had obtained substantial benefits from cytotoxic therapy. Although the regimen reported in the current study can become an attractive option for many patients with carcinoma of unknown primary site, there remains a need for further clinical trials.

Bone marrow origin of a B-cell lymphoma.

To search for precursors of the neoplastic B cells in a patient with a nodular lymphoma, we produced a monoclonal antibody to a variable region idiotope on the lymphoma IgM heavy chain. Clonal ancestors of the lymphoma cells were identified by this marker among bone marrow pre-B cells (5% to 26%). A second antiidiotype (anti-Id) antibody specific for the complete lymphoma IgM kappa recognized 10% of B cells in bone marrow and blood and greater than 95% of B cells in lymphomatous lymph nodes, including one obtained after tumor conversion to a diffuse large cell lymphoma. Immunoglobulin gene analysis surprisingly revealed expansion of multiple clones of early B lineage cells in bone marrow, including members of the neoplastic clone. The data suggest that this lymphoma arose through a progression of transformational events beginning in bone marrow: first, creation of an oligoclonal pre-neoplastic pool of pre-B cells, subsequent conversion of a single subclone into low grade neoplastic B cells that homed to the lymph node follicles, and later progression to a more invasive form of the B-cell lymphoma.

Prevalence of hepatitis B in selected Alaskan Eskimo villages.

Sera collected in 1973-1975 from 3053 residents of 12 selected Alaskan Eskimo villages were tested for evidence of hepatitis B virus infection. Overall, hepatitis B surface antigen (HBsAg) was found in 6.4% of those tested. Evidence of hepatitis B infection (positive for HBsAg or antibody to hepatitis B surface antigen (anti-HBs] varied considerably by village, from 4.6% to 69.9%, and increased with advancing age. The proportion with HBsAg was significantly higher in those under the age of 13 years, and the male/female ratio varied from 0.9 to 1.5 to 1.5 in the prepubertal, postpubertal-premenopausal, and postmenopausal age groups, respectively. The prevalence of hepatitis B e antigen (HBeAg) in HBsAg-positive persons decreased with advancing age, and conversely, the prevalence of antibody to hepatitis B e antigen (anti-HBe) increased with age. Hepatitis B infection was found to be sporadically distributed, with great village-to-village variation and further variation by household within most villages. The high HBsAg and HBeAg seropositivity observed in children suggests that children are both more recently infected with hepatitis B and are more involved in hepatitis B transmission in these villages.

Clinical experience with ciprofloxacin: analysis of a multicenter study.

In a multicenter study of 128 patients treated with ciprofloxacin (mean daily dosage, 982 mg per day; mean duration of treatment, 8.9 days) for a variety of infections, 48 were microbiologically proven. Of these, bacteriologic cure and/or improvement resulted in 93% of cases. For all 128 infections clinical cure and/or improvement resulted in 93.8% of cases. Twenty-nine (23.8%) of all infections were classified as chronic. Overall, there were 3/128 (2.3%) adverse reactions (ADRs); one case each of diarrhea, malaise, and nausea/vomiting. None were related definitely to ciprofloxacin therapy. Therapy with ciprofloxacin was discontinued in two (1.6%) of 128 patients because of adverse gastrointestinal (GI) effects. One patient elected to continue ciprofloxacin therapy despite mild GI side effects.

Hepatitis B in homosexual men: prevalence of infection and factors related to transmission.

Of 3,816 homosexual men examined in five sexually transmitted disease clinics in the United States, 6.1% had hepatitis B surface antigen, 52.4% had antibody to hepatitis B surface antigen, and 3.0% of the men who had no other indicator of infection with hepatitis B virus (HBV) had antibody to hepatitis B core antigen. The rate of seropositivity for HBV indicated by the presence of one or more of these serologic markers was 61.5%; seropositivity was significantly related to the duration of regular homosexual activity and to the number of nonsteady male sexual contacts in the four months before the patients were interviewed. Anal-genital intercourse, oral-anal intercourse, and rectal douching were significantly related to evidence of HBV infection, but oral-oral contact and oral-genital contact were not. Trauma to the rectal mucosa is a feature common to the practices that were significantly related to seropositivity for HBV.