Efficacy, toxicity, and pharmacokinetics of pentoxifylline and its analogs in experimental Staphylococcus aureus infections.

Pentoxifylline (PTX), a drug that improves neutrophil function in vitro, has been shown to protect neonatal mice against death from experimental staphylococcal infection in vivo at a dose of 50 mg/kg. Using a total of 774 neonatal mice, the effects of various doses of PTX were examined and compared with the effects of three analogs: HWA-448, HWA-285, and A81-3138. A subcutaneous abscess was induced with 10(8) Staphylococcus aureus, and drug or saline was given daily subcutaneously from 2 days before to 4 days after infection. Noninfected animals (given saline without S. aureus) had 0% mortality (0 of 66), and infected animals without drug (given saline) had a mortality of 70% (161 of 231). PTX and HWA-448 showed the greatest protection among the drugs tested at 15 mg/kg with mortality rates of 27 and 38%, respectively (Kaplan-Meier method, P = 0.0001 and 0.0004, respectively). HWA-285 was most protective at 25 mg/kg (mortality, 45%; P = 0.0046) and A81-3138 was most protective in animals at 15 mg/kg (mortality, 42%; P = 0.0045). PTX, HWA-448, HWA-285, and A81-3138 at doses of 200, 100, 100, and 50 to 75 mg/kg, respectively, were toxic as shown by worsened weight loss and increased mortality in animals when compared with infected animals without drug. PTX and its analogs decrease mortality from experimental infections at lower doses but are toxic at higher doses. Pharmacokinetic characteristics of the drugs were similar except that HWA-285 produced lower concentrations in serum and A81-3138 showed a dose-dependent kinetics (longer half-life at a higher dose).

Pitfalls in testing drug uptake by leukocytes using radiolabeled drugs and an explanation of conflicting results with clindamycin.

Although studies of drug uptake by leukocytes use similar methods, the results reported are sometimes vastly different. To determine the possible reasons for this, we studied neutrophil uptake of [3H]-clindamycin using the most frequently used density gradient centrifugation method and the volume probes 3H2O and [3H]-polyethylene glycol. We found that the [3H]-clindamycin available to investigators had undergone radiolytic decomposition; thus, its microbiologic activity was only 20% of its original potency. By thin-layer chromatography and autoradiography, four extra label-bearing regions were observed with [3H]-clindamycin. Results of neutrophil uptake studies have shown a drop of cellular:extracellular concentration ratios from 40:1 in 1981 to 10:1 in 1982 and 1987.

High teicoplanin uptake by human neutrophils.

The cellular/extracellular (C/E) concentration ratio of teicoplanin in polymorphonuclear leukocytes (PMNs) increased rapidly with time (C/E 60 +/- 13 at 20 min). The C/E ratio was time- and concentration-dependent. At 20 min and an initial concentration of 75 +/- 16 micrograms/ml the cellular drug concentration was 4,700 +/- 1,300 micrograms/ml. The mechanism of drug uptake was by an active process and transported (cellular) drug retained its antimicrobial activity. Washing removed 42% of cellular drug. Teicoplanin inhibited PMN chemotaxis at very high concentrations and PMN microbicidal activity at lower concentrations.

Inappropriate activation, deactivation, and probable autooxidative damage as a mechanism of neutrophil locomotory defect in trauma.

We studied 46 patients who suffered from serious blunt trauma to examine the possible mechanism of their acquired neutrophil (PMN) locomotory dysfunction. Concentrations of plasma C3adesArg were higher in patients than in controls (310 +/- 190 ng/ml vs. 90 +/- 28 ng/ml, respectively; P = 3 X 10(-5)). Both resting and phagocytosing PMNs from the patients produced higher quantities of H2O2 (0.31 +/- 0.29 and 5.2 +/- 3.4 nmol/10(6) PMNs per hr, respectively). These levels resemble the H2O2 production of normal PMNs preactivated with chemotactic factor (0.85 +/- 0.03 for normal and 8.2 +/- 1.6 nmol/10(6) PMNs per hr for preactivated PMNs). Concentrations of oxidized glutathione were not significantly higher in PMNs from patients compared with PMNs from controls (0.053 +/- 0.057 vs. 0.037 +/- 0.046 nmol/10(6) PMNs, respectively; P = .5). A higher percentage of PMNs from trauma patients than from controls were capped with concanavalin A (66% +/- 11% vs. 37% +/- 14%, respectively; P = 4 X 10(-5)), a result indicating microtubular dysfunction. These findings suggest that in trauma, activation of intravascular complement results in inappropriate chemotactic stimulation and subsequent deactivation and autoxidative damage of circulating PMNs.

Protective effects of ibuprofen and methylprednisolone on chemotactic factor-induced transcutaneous hypoxia.

We showed previously in vitro that ibuprofen, a nonsteroidal anti-inflammatory agent, at concentrations easily achievable in blood, inhibits polymorphonuclear leukocyte cell swelling and aggregation in response to chemotactic factor stimulation. To confirm this in vivo, we studied the ability of ibuprofen i.v. pretreatment to reverse the transcutaneous hypoxia induced by i.v. infusion of 1 nmol/kg of formyl-methionyl-leucyl-phenylalanine. This effect was compared with that of methylprednisolone. For ibuprofen and methylprednisolone, respectively, the maximum percentage of reversal of hypoxia was 85 and 106%; the dose required to produce 50% of maximum reversal was 2.7 and 4.6 mg/kg; and the serum drug concentration needed to achieve 50% of maximum reversal was 14 and 11 micrograms/ml. We conclude that ibuprofen could be a useful alternative to steroidal antiinflammatory agents for the prevention and treatment of complications of stimulated polymorphonuclear leukocytes.

The need for elective irradiation of occult lymphatic metastases from cancers of the larynx and pyriform sinus.

The incidence of palpable and occult cancer and the absence of cancer in lymph nodes were determined for individual sites in the larynx and pharynx of 540 patients who underwent neck dissection. The incidence of palpable cancer in lymph nodes was lowest for cancers of the central supraglottis and transglottis (32-41%), intermediate for cancers of the marginal supraglottis and glossoepiglottis (48-57%), and highest for cancers of the pyriform sinus (69%). The incidence of occult cancer in lymph nodes for individual sites in the larynx and pharynx was determined by pathologic study of neck dissection specimens from 253 patients without palpable lymph nodes (NO neck). The incidence of occult lymphatic metastases in the NO neck and the need for elective neck irradiation were least for cancers of the transglottis and central supraglottis (14-16%), intermediate for cancers of the glossoepiglottis and the marginal supraglottis (20-38%), and greatest for cancers of the pyriform sinus (47%). The risk of nodal recurrence increased from 8% for those without cancer in lymph nodes to 38% for those with occult or palpable cancer in lymph nodes. A policy of observing the NO neck in patients with a low incidence of occult lymphatic metastases and a low risk of neck recurrence to avoid the unnecessary irradiation of many to benefit a few is discussed.

Treatment of stage I adenocarcinoma of the endometrium by hysterectomy and irradiation: analysis of complications.

Twelve of 304 patients (4%) treated with surgery and adjuvant irradiation for endometrial carcinoma experienced a serious complication. The complication rate for patients whose irradiation consisted of an implant alone was only 1% (two of 199), if the implant was preoperative, but was 12% (three of 26) if the implant was postoperative. For patients who received external pelvic irradiation as part of their adjuvant therapy, the incidence of complications was 8.8% (seven of 79) and the timing (preoperative versus postoperative) had no effect. There was, however, a significant correlation of the complication rate with an increasing dose of external irradiation to the whole pelvis: For doses of 3000 rad or less, it was 2% (five of 264) but was 18% (seven of 40) for doses in excess of 3000 rad. These data suggest that the safest form of adjuvant irradiation for adenocarcinoma of the endometrium is a preoperative implant, and that adding external pelvic irradiation to the preoperative implant will significantly increase the complication rate if the external dose to the central pelvis exceeds 3000 rad.

Inhibition of human polymorphonuclear leukocyte cell responses by ibuprofen.

The stimulation of cell swelling, cell aggregation, polymorphonuclear leukocyte locomotion, and lysosomal enzyme release in response to chemoattractant were all inhibited by ibuprofen, a nonsteroidal anti-inflammatory agent. The dosages needed to induce 50% inhibition (ID50) were 5.9, 7.6, 60, and 95 micrograms/mL, respectively. Aside from the differences in ID50, there was also a difference in the degree of maximum inhibition (Imax) of the complement C5a-stimulated responses observed, so that at achievable serum drug concentrations of 20-50 micrograms/mL, inhibition of 67-78% for cell swelling, 69-82% for cell aggregation, 20-35% for migration response, and 17-38% for lysosomal enzyme release were demonstrated. Also observed were a minor stimulatory effect on nitroblue tetrazolium reduction and an inhibitory effect on the ability to kill Staphylococcus aureus, but only at very high concentrations (approximately 2 mg/mL).

Pitfalls in the use of death certificates for assessing cause of death: a study of tonsil carcinoma patients.

A study was undertaken to determine the accuracy of underlying cause of death as stated on the death certificate for patients treated at Mallinckrodt Institute of Radiology (MIR) for carcinoma of the tonsil. The sample consisted of 110 patients who were treated between 1953 and 1976 and who subsequently died; all patients were seen by a physician within 3 months of their death. Death certificate cause of death was compared with the cause of death as stated in the MIR patient record. Death certificates detected 42.5% of the deaths due to tonsil carcinoma recorded in the hospital record, and detection was found to correlate with time between treatment and death. Of the deaths reported on the death certificate as due to tonsil carcinoma, 91% were confirmed by the hospital record to be correctly reported. Overall agreement in assignment of cause of death between the hospital record and the death certificate was 59%, and was significantly affected by stage of disease at diagnosis. This review underscores the low reliability of death certificates and raises a serious question concerning the use of this information for patients who are registered in clinical trials without additional documentation of tumor extent and cause of death.

Radiation therapy alone in the treatment of carcinoma of the uterine cervix. II. Analysis of complications.

A retrospective analysis was carried out on 811 patients with histologically proven invasive carcinoma of the uterine cervix treated with irradiation alone. A correlation was made of the doses of irradiation delivered to the pelvic organs with external beam and intracavitary insertions. Approximately 3% of the patients exhibited grade 2 gastrointestinal complications, and 2% developed grade 2 urinary complications; 5% of the patients developed grade 3 gastrointestinal complications, and 3% developed grade 3 urinary complications. Other types of complications, primarily grade 2, such as vaginal necrosis, pelvic abscess, thrombophlebitis, etc, were seen in approximately 5% of the patients. Thus, the total percentage of patients developing grade 2 complications was 10% and grade 3 complications, approximately 8%. About 25% of the patients who had complications showed more than one sequela. The most frequently observed grade 2 complications were proctitis, cystitis, vaginal stenosis, and partial small bowel obstruction which were treated with conservative management. Grade 3 complications required surgical treatment and consisted most frequently of ureteral stricture, vesicovaginal fistula, rectovaginal fistula, sigmoid stricture, small bowel obstruction, proctitis, and large rectal ulcers. The most significant factor affecting the appearance of complications was the total dose of irradiation delivered to the pelvic organs by the whole pelvis external irradiation and intracavitary insertions. With maximum total doses up to 8000 rad the incidence of grade 2 and 3 complications was less than 5%. However, with higher doses the incidence of complications increased to 10% to 15%. In patients receiving total doses of 6000 rad to the bladder or rectum, more complications were noted when only one intracavitary insertion was performed, as compared with two or three. Eighty percent of the rectosigmoid complications occurred within 30 months of initial therapy, in contrast to 48 months for the urinary complications. Patients who developed complications had survival rates comparable to those without complications. This underscores the need to rapidly institute treatment on patients who have severe injury after radiation therapy.(ABSTRACT TRUNCATED AT 400 WORDS)

Accrual of radiotherapy patients to clinical trials.

Recruitment of patients to clinical trials is a multi-stage process. To participate in a protocol, a patient must meet all the eligibility requirements; the physicians managing the patient must be amenable to enrolling the patient on protocol; and finally, the patient must consent to participate. In 1979, 64 clinical trials were open to patient accrual in the Division of Radiation Oncology, Mallinckrodt Institute of Radiology, St. Louis, Missouri. A total of 1103 cases were reviewed. Two hundred sixty-three patients were eligible for one of the protocols, of whom 124 were successfully recruited. The reasons for ineligibility and nonparticipation are discussed.

Radiation therapy alone in the treatment of carcinoma of uterine cervix. I. Analysis of tumor recurrence.

This is a retrospective analysis with emphasis on the patterns of failure in 849 patients with histologically proven invasive carcinoma of the uterine cervix treated with irradiation alone. In 281 patients with Stage IB tumors, the total incidence of pelvic failure was 6.4% (two without and 16 combined with distant metastasis). In 88 patients with Stage IIA, 12.5% failed in the pelvis (one without and ten combined with distant metastasis). The total pelvic failure rate in Stage IIB was 17.4% (22 without and 22 combined with distant metastasis). In 212 patients with Stage III, the overall pelvic failure rate was 35.8% (31 without and 45 combined with distant metastasis). Approximately 25% of the pelvic recurrences were central (cervix or vagina) and 75% parametrial. The overall incidence of distant metastasis was 13.5% for Stage IB, 27.3% for Stage IIA, 23.8% for Stage IIB, and 39.6% in Stage III. Higher doses of irradiation delivered to the medial and lateral parametrium with external beam irradiation and intracavitary insertions were correlated with a lower incidence of parametrial failures in all stages, except IB. In Stage IIA, medial parametrial doses below 9000 rad resulted in 10/78 = 12.8% pelvic failures, in contrast to one recurrence in 10 patients treated with doses over 9000 rad. In Stage IIB, doses below 9000 rad yielded a pelvic recurrence rate of 36/203 (17.7%) compared to 5/49 (10.2%) with higher doses. In Stage III there were 66/167 (39.5%) recurrences with doses below 9000 rad and 10/44 (22.7%) with larger doses. Statistically significant differences were observed among the Stage IIB (P = 0.02) and III patients (P = 0.005) respectively. The lateral parametrial dose also showed some correlation with tumor control, although the differences were not statistically significant. The survival in patients with Stage IIB and III was 10% higher in the patients treated with higher parametrial doses. However, the differences are not statistically significant. These results strongly suggest that higher doses of irradiation must be delivered to patients with Stage IIB and III, but improvement in tumor control must be weighed against an increasing number of complications. Factors other than the total doses of irradiation, such as the characteristics of the tumor and the quality of the intracavitary insertion influence the therapeutic results in irradiation of carcinoma of the uterine cervix. Other therapeutic approaches must be designed to improve the effect of irradiation in the tumor without further injury to the normal tissues. Hypoxic cell sensitizers, hyperthermia and high LET particles are under investigation.

Renal graft irradiation in acute rejection.

To evaluate the effect of graft irradiation in the treatment of acute rejection of renal transplants, a randomized study was conducted from 1978 to 1981. Patients with acute rejection were given standard medical management in the form of intravenous methylprednisolone, and were chosen randomly to receive either graft irradiation (175 rads every other day, to a total of 525 rads) or simulated (sham) irradiation. Eighty-three rejections occurring in 64 grafts were randomized to the protocol. Rejection reversal was recorded in 84.5% of control grafts and 75% of the irradiated grafts. Recurrent rejections were more frequent and graft survival was significantly lower in the irradiated group (22%) than in the control group (54%). Graft irradiation does not appear to be beneficial in the treatment of acute rejection of renal transplants when used in conjunction with high-dose steroids.

Endometrial extension of carcinoma of the uterine cervix: a prognostic factor that may modify staging.

A retrospective review was done of 473 patients with histologically proven primary carcinoma of the uterine cervix on whom a dilatation and curettage (D & C) was performed during the initial workup. The pathologic features of the D & C specimens were classified as: (1) endometrial stomal invasion of cervical carcinoma; (2) tumor only, cervical carcinoma in D & C, normal endometrium absent; (3) admixture of normal endometrium and cervical carcinoma (contamination); (4) D & C negative for tumor. The patients were staged according to the FIGO classification. Eighty-two percent (388) of the patients were treated with radiation alone and the rest with a combination including surgical procedures (usually radical hystrectomy with lymphadenectomy). The three- and five-year survival rates were 10% to 20% lower for patients with D & C showing stromal invasion or tumor only than in patients with admixture or negative D & C. These results were coupled with an appreciably higher number of distant metastases in the patients with positive D & C and a lower incidence in patients with negative D & C. The authors suggest that endometrial extension of carcinoma of the uterine cervix may be an important factor in the staging classification of these patients and recommend that D & C always be done in the initial evaluation. Because of the high incidence of distant metastasis, effective adjuvant therapy must be developed to improve the present therapeutic results.

Irradiation alone or in combination with surgery in stage IB and IIA carcinoma of the uterine cervix: A nonrandomized comparison.

This is a report of a nonrandomized comparison of treatment results of 244 patients with stage IB carcinoma of the uterine cervix treated by radiation alone and 92 treated with preoperative radiation and surgery and 77 patients with stage IIA treated by radiation alone and 24 treated with a combination of radiation and surgery. The techniques of irradiation and types of operation are described in detail. The five-year tumor free actuarial survival for the patients with stage IB treated either with irradiation alone or combined with surgery was approximately 85% and the ten-year survival, 78%. For stage IIA the tumor free actuarial five-year survival without tumor was 73% and for ten years, 60%. In the 244 patients treated with radiation alone, there were ten central failures (4%) usually combined with distant metastasis. Further, 16 of these patients (6.5%) developed parametrial recurrence, in all but one instance associated with distant metastasis. In the 92 patients with stage IB treated with combined therapy, there were three local recurrences (3.8%), two of them combined with parametrial failures and six parametrial recurrences (6.5%), all of them concomitant with distant metastasis. Of the 77 patients with stage IIA treated by irradiation alone, there was one central recurrence alone and five local and parametrial recurrences, all of them associated with periaortic nodes or distant metastasis. Four additional patients had parametrial recurrences only concurrent with distant metastasis. Of the 24 patients treated with irradiation and surgery, there were two parametrial recurrences combined with distant metastasis (8.2%). There was no significant difference in the survival or recurrence rate of the patients treated with either method. In the group treated with combined therapy, patients with stage IB who showed evidence of microscopic residual tumor after irradiation had a failure rate of approximately 42% (8/18) in contrast to only 8.6% (6/70) in those with negative specimens. In stage IIA there were three failures in eight patients with residual tumor in the specimen in contrast to only two of 16 with negative specimens (12.5%). Major complications were comparable in both groups (radiation alone approximately 8.7% and irradiation combined with surgery approximately 14%), the difference is not statistically significant. The most frequent minor complication in patients treated with radiation alone was vaginal fibrosis (30 patients--9%) or vaginal vault necrosis (10 patients--3%).