Circadian function in patients with advanced non-small-cell lung cancer.

This study aimed to evaluate whether patients with advanced non-small-cell lung cancer experience disrupted rest-activity daily rhythms, poor sleep quality, weakness, and maintain attributes that are linked to circadian function such as fatigue. This report describes the rest-activity patterns of 33 non-small-cell lung cancer patients who participated in a randomised clinical trial evaluating the benefits of melatonin. Data are reported on circadian function, health-related quality of life (QoL), subjective sleep quality, and anxiety/depression levels prior to randomisation and treatment. Actigraphy data, an objective measure of circadian function, demonstrated that patients' rest-activity circadian function differs significantly from control subjects. Our patients reported poor sleep quality and high levels of fatigue. Ferrans and Powers QoL Index instrument found a high level of dissatisfaction with health-related QoL. Data from the European Organization for Research and Treatment for Cancer reported poor capacity to fulfil the activities of daily living. Patients studied in the hospital during or near chemotherapy had significantly more abnormal circadian function than those studied in the ambulatory setting. Our data indicate that measurement of circadian sleep/activity dynamics should be accomplished in the outpatient/home setting for a minimum of 4-7 circadian cycles to assure that they are most representative of the patients' true condition. We conclude that the daily sleep/activity patterns of patients with advanced lung cancer are disturbed. These are accompanied by marked disruption of QoL and function. These data argue for investigating how much of this poor functioning and QoL are actually caused by this circadian disruption, and, whether behavioural, light-based, and or pharmacologic strategies to correct the circadian/sleep activity patterns can improve function and QoL.

A pregnant pause: blunt urologic trauma in a young woman.

Trauma in a woman of child-bearing age is rarely discussed in urologic literature. However, it is the leading cause of maternal death during pregnancy. We propose that the standard workup for gross hematuria secondary to trauma be performed, in light of child-bearing age, since the greatest cause of fetal demise in this setting is maternal death.

Phase I trial of recombinant human macrophage colony-stimulating factor administered by continuous intravenous infusion in patients with metastatic cancer.

BACKGROUND: Macrophage colony-stimulating factor is a bone marrow-derived glycoprotein that can stimulate monocytes and macrophages, resulting in production of factors involved in immune response. In vitro and in vivo preclinical studies in animals have demonstrated that recombinant human macrophage colony-stimulating factor (rHuM-CSF) can have antitumor activity. PURPOSE: A phase I clinical trial was undertaken to evaluate the toxicity, pharmacokinetics, and immunologic effects of rHuM-CSF given by continuous intravenous infusion in patients with cancer. METHODS: Eighteen patients with metastatic solid tumors refractory to conventional therapy were treated with rHuM-CSF. Twelve patients received two 14-day cycles of rHuM-CSF by continuous infusion, with a 2-week interval. Dose escalation levels were 50, 100, and 150 micrograms/kg over 24 hours. Consecutive cohorts of three to six patients were planned at each dose level. Six patients received a modified regimen of four 7-day periods of infusion at 100 micrograms/kg over 24 hours, with 1-week intervals. RESULTS: Dose-limiting toxicity was grade 4 thrombocytopenia at a dose of 150 micrograms/kg over 24 hours in two patients receiving the 2-week regimen. Platelet count nadirs and concomitant monocytosis were seen on days 7-9, but recovery occurred during the treatment period. Macrophage colony-stimulating factor serum levels were maximal on day 1 and returned to near baseline on day 7 of infusion. Patients treated with four 7-day infusions had no treatment-limiting thrombocytopenia. There were no cumulative effects on platelet or monocyte counts or significant constitutional symptoms. Subclinical conjunctival injection was noted in five of 10 patients receiving screening ophthalmologic evaluation. Grade 2 episcleritis was diagnosed in one patient, and asymptomatic perilimbal and retinal hemorrhages were seen in two. Two patients developed sepsis caused by the intravenous line, which required cessation of therapy. No objective responses were documented. CONCLUSION: The maximum tolerated dose of rHuM-CSF given by continuous intravenous infusion for 14 days was 100 micrograms/kg over 24 hours, with rapidly reversible, dose-limiting thrombocytopenia at 150 micrograms/kg over 24 hours. A regimen alternating weekly cycles of infusion avoids dose-limiting toxicity and allows long-term treatment. IMPLICATIONS: The regimen of repeated 7-day infusions may be useful for future studies evaluating rHuM-CSF-activated monocytes in therapy for long-term infectious diseases or in investigation of new modes of cancer therapy using rHuM-CSF in conjunction with a tumor-specific antibody.

Fluorodeoxyuridine with continuous leucovorin infusion. A phase II clinical trial in patients with metastatic colorectal cancer.

BACKGROUND: Chemotherapy of colon cancer has used the modulation of 5-fluorouracil (5-FU) by leucovorin; however, early studies indicate that leucovorin with fluorodeoxyuridine (FUDR) may be clinically superior. The authors report their experience in patients with metastatic colorectal cancer. METHODS: One hundred twelve evaluable patients with metastatic colorectal cancer were treated with leucovorin and FUDR. Leucovorin was given by continuous intravenous infusion at 500 mg/m2/day on days 1-6, and FUDR was given by intravenous push on days 2-6 at 3:00 p.m. daily, with doses ranging from 270-1350 mg/m2/day. RESULTS: This regimen was well tolerated with dose-limiting toxicity of diarrhea and stomatitis, while hematologic toxicity was minimal. At least one chemotherapy regimen had previously failed in 90 of 112 patients (80%). Twenty major responses greater than or equal to partial remission, lasting from 2-40+ months, were observed in this patient population for an overall response rate of 18%. Twelve of 22 previously untreated patients (55%) had major responses. Overall survival of previously untreated patients was 73% (14 of 19) and 50% (11 of 22) at 1 and 2 years, respectively. Of 66 patients who had received prior leucovorin-5-FU (LVFU) therapy with subsequent disease progression, 4 had major responses lasting 95, 241, 350, and 432 days, respectively. CONCLUSIONS: These data suggest that the modulation of FUDR by leucovorin may have clinical use. The recommended starting dose of FUDR is 800 mg/m2/day on days 2-6, with subsequent escalation each month in those patients who do not display stomatitis.

[Intracavernous pharmacotherapy for treatment and evaluation of impotence].

Impotence affects about 10% of all men. During the past decade it has been treated with self-injection of vasoactive drugs into the erectile tissue. In 1982 Virag reported experience with intracavernous injection of papaverine. Since then other vasoactive drugs, such as prostaglandin E1 (PGE1), have been used successfully, and self-injection has been advised. Between 1987-1989 we evaluated 550 patients with erectile dysfunction and 95 aged 21-79, mean 53.7, were found suitable for this treatment, of whom 80 were entered into an autoinjection protocol, of 74 were treated with a mixture of papaverine and regitine and 6 with PGE1. The volume of the injections ranged from 0.1 to 1.0 ml, and erections lasted from 15 minutes to 8 hours. 72% of the patients continued autoinjection during a mean follow-up of 9.9 months and were satisfied with the results. There were 5 cases of corporal fibrosis, and 3 cases had prolonged erections, usually after the papaverine test. The method is simple and inexpensive, and allows many impotent men to resume sexual life. It is a good alternative to the insertion of a penile prosthesis.

Phase I clinical trial with floxuridine and high-dose continuous infusion of leucovorin calcium.

Sixty-two patients with metastatic disease were treated with continuous infusion folinic acid (leucovorin calcium; Lv) and 2-deoxy-5-fluorouridine (floxuridine; FUDR). Lv was given by constant intravenous (IV) infusion at 500 mg/m2/d, days 1 to 6, while FUDR was given by IV push, days 2 to 6, at 3:00 PM daily with doses ranging from 294 to 1,214 mg/m2/d. This program was well tolerated with dose-limiting toxicities of diarrhea and stomatitis, while hematologic toxicity was minimal. Eighty-two percent of the assessable patients (46 of 56) had failed at least one chemotherapy regimen. One complete remission lasting 9 months and 10 partial remissions ranging from 5 to 10 months were observed in this heavily pretreated patient population for an overall response rate of 20%. These data suggest that the combination therapy with Lv and FUDR may have clinical use. Because of differing patient sensitivity to this drug combination, the recommended dose of FUDR for the initial therapy cycle is 500 mg/m2/d, days 2 to 6, with subsequent escalation to 900 mg/m2/d in those patients without extreme sensitivity. Phase II studies are now in progress with these doses.

Relative efficacy and toxicity of netilmicin and tobramycin in oncology patients.

We prospectively compared the efficacy and safety of netilmicin sulfate or tobramycin sulfate in conjunction with piperacillin sodium in 118 immunocompromised patients with presumed severe infections. The two treatment regimens were equally efficacious. Nephrotoxicity occurred in a similar proportion in patients treated with netilmicin and tobramycin (17% vs 11%). Ototoxicity occurred in four (9.5%) of 42 netilmicin and piperacillin and in 12 (22%) of 54 tobramycin and piperacillin-treated patients. Of those evaluated with posttherapy audiograms, three of four netilmicin and piperacillin-treated patients had auditory thresholds return to baseline compared with one of nine tobramycin and piperacillin-treated patients. The number of greater than or equal to 15-dB increases in auditory threshold as a proportion of total greater than or equal to 15-dB changes (increases and decreases) was significantly lower in netilmicin and piperacillin- vs tobramycin and piperacillin-treated patients (18 of 78 vs 67 of 115). We conclude that aminoglycoside-associated ototoxicity was less severe and more often reversible with netilmicin than with tobramycin.

Suppression of B-lymphocyte function by T-lymphocytes in patients with advanced lung cancer.

The ability of B-lymphocytes to produce immunoglobulins in response to pokeweek mitogen stimulation was studied in 21 untreated stage III lung cancer patients by culture of their mononuclear cells in vitro. The number of immunoglobulin-producing cells was significantly lower in 20 of the 21 patients when compared to responses shown by normal control subjects. In contrast, the proliferative responses of many of the patients were within the normal range. When the T-lymphocytes of these patients were irradiated with 1,250 rad to eliminate the suppressor T-cell activity and then cultured with autologous B-cells, the number of immunoglobulin-producing cells was enhanced to the normal range in 7 of the 18 patients. These results indicate that B-cell function is impaired in most patients with advanced lung cancer. They also suggest that, in addition to suppression by radiosensitive suppressor T-cells, other mechanisms are involved in the observed B-cell functional abnormality.

Subpopulation of human helper and suppressor T lymphocytes.

Mitogen driven differentiation of normal human mononuclear cells is a well-established model for the study of antibody synthesis in man. In certain rare individuals who are clinically normal, unfractionated mononuclear cells or a mixture of purified B plus T lymphocytes differentiate into immunoglobulin producing cells in response to purified protein derivative of tuberculin (PPD) but not in response to pokeweed mitogen (PWM). To evaluate this observation we have irradiated T cells from such individuals to eliminate naturally occurring suppressor T cell activity and then added the irradiated T cells back to autologous B cells before culture. The B cells then responded to PWM. The original PPD responses of cells from these individuals were now significantly reduced. Although, there was no difference between PWM nonresponders and responders in the number of OKT-8 positive cells, elimination of OKT-8 positive cells in the PWM nonresponders with OKT-8 monoclonal antibody and complement resulted in a significantly increased response to PWM. This study indicates that there are suppressor T cells which specifically inhibit B cell response to PWM without affecting the PPD response. These results also show that the helper T cells involved in the PWM response are radioresistant and those involved in the PPD response are radiosensitive.

Studies of retinopathy and the plasma co-factor of platelet hyperaggregation in type 1 (insulin-dependent) diabetic children.

Only one out of 73 children with young-onset Type 1 (insulin-dependent) diabetes for less than 10 years had retinopathy detectable with fluorescein retinal angiography. Although these fluorescent studies were normal, retinal abnormalities were detected in 19 out of 53 patients by electro-retinography and in four out of 28 patients by the 100-hue colour test. We were unable to confirm recent reports indicating that most Type 1 diabetic patients have retinopathy detectable by fluorescein angiography. The diabetic plasma co-factor induces normal platelets to hyperaggregate in vitro. Plasma co-factor activities in adult diabetic patients have previously been shown to correlate with the degree of hyperaggregation, although in general, only those patients with severe retinopathy or nephropathy have high plasma activities. The plasma activities of 192 Type 1 diabetic patients were significantly higher than those of normal subjects (p less than 0.01). Of ten children with markedly elevated activities, nine did not have retinopathy.

Partial purification and studies of the plasma co-factor that potentiates platelet aggregation in diabetes mellitus.

A co-factor is present in the plasma of some diabetics that potentiates the degree of in vitro aggregation of normal platelets after ADP stimulus. This paper presents important changes in the analysis technique that utilize recently appreciated knowledge about platelet aggregation and that were needed to permit characterization of the co-factor. By this new technique, the plasma co-factor activity of 33 normal adults and 43 normal children was significantly lower (p less than 0.001) than that of the corresponding diabetic groups. Thirty-two percent of the adult and 23% of the child diabetics had an elevated plasma co-factor activity. None of the 71 diabetic children and only 12 of the 65 diabetic adults had severe retinopathy. These results correlate well with previous reports wherein the plasma co-factor activity was highest in patients who had severe retinopathy or nephropathy and was usually normal when microangiopathy was not evident. The co-factor was completely precipitated from the plasma of a diabetic with ammonium sulfate at the concentration of 34% of saturation. An aqueous solution of this precipitate retained co-factor activity during incubation at 56 degrees for 30 min but lost activity at neutral pH conditions. Co-factor activity eluted during gel filtration to indicate an estimated molecular weight of 21,000 daltons. The improved technique reported here should facilitate study of the platelet hyperaggregation co-factor and the pathophysiology of diabetic microangiopathy.

Fibrinolysis in familial pulmonary hypertension.

Although an autosomal dominant mode of inheritance has been documented for many cases of primary pulmonary hypertension, the pathogenesis of the disease remains unclear. A report of abnormal fibrinolysis in familial pulmonary hypertension has raised the possibility that the pathogenesis may be related to an impaired ability to lyse recurrent pulmonary microemboli. Primary pulmonary hypertension was diagnosed in three of ten members of a kindred. The pattern of inheritance was compatible with an autosomal dominant gene. Eight members of the kindred were available for study, one of whom has primary pulmonary hypertension. The results of coagulation studies, caseinolytic determinations of plasminogen and antiplasmin, and fibrinolytic titers of antiurokinase did not differ significantly from those of the control group. These findings suggest that a deficient fibrinolytic system is not the cause of primary pulmonary hypertension, although differences in methodology may explain our inability to demonstrate abnormal circulating fibrinolysis in this kindred.

Changes in platelet function during hemodialysis.

Platelet function was studied in 34 patients during 74 hemodialyses by means of a Cordis-Dow hollow fiber hemodialyzer (CDAK-4) with anticoagulation by porcine mucosal heparin. The mean arterial platelet levels fell 11% from predialysis values and remained stable throughout a 5 hr hemodialysis session. After 30 min of dialysis, the platelet concentration in afferent and efferent limbs of the dialyzer were similar, although retention of leukocytes was apparent. As measured by platelet aggregometry, heparin was clearly shown to potentiate the extent of aggregation induced by low concentrations of ADP. Platelets of the dialyzer afferent limb were less aggregable than normal and resistant to aggregation induced by submaximal concentrations of ADP or epinephrine. Platelets of the dialyzer efferent limb were aggregable only after excessive stimuli of 50 micrometer ADP or 10 micrometer epinephrine. These findings suggest that direct contact between dialyzer fibers and platelets or rheological effects led to impaired platelet function but that most platelets are not irreversibly injured.

Return of function in the thrombosed kidney after transplantation.

The incidence of intraglomerular thrombi in renal allografts and factors regulating their resolution were studied. A case report is presented in which resolution of intraglomerular thrombi is documented. In addition, 17 transplanted patients with renal biopsies were serially studied. Intraglomerular thrombi were found in 4 of 8 specimens taken 1 h after reanastamosis, all from donors with a terminal course involving prolonged hypotension. Glomerular fibrinolytic activity was markedly diminished in 4 of 11 patients' subsequent biopsy specimens; all taken during acute rejection. Resolution of thrombi was documented when signs of rejection were absent.