Buccal adherence of Pseudomonas aeruginosa in patients with cystic fibrosis under long-term therapy with azithromycin.

BACKGROUND: The oropharyngeal barrier is an innate host defence mechanism to prevent bacterial Lung infection. A compromised barrier function is observed in patients with cystic fibrosis (CF) who are chronically infected with Pseudomonas aeruginosa. Macrolides are assumed to modify host defence. We investigated the oropharyngeaL barrier function in CF patients treated with azithromycin (AZM). PATIENTS AND METHODS: In a prospective study, eleven chronically infected children with CF were treated with longterm low-dose AZM. The oropharyngeal barrier function was assessed by adherence of P. aeruginosa (strain PACF 12-1) to buccal epithelial cells of the patients before and after therapy. RESULTS: The mean (standard deviation, SD) buccaL adherence before therapy was markedly high with 8.0 (4.8) bacteria/cell. Following therapy with AZM adherence decreased in all patients by 70% or 5.6 to 2.4 (1.1) bacteria/cell (p = 0.007), representing close to normal LeveLs (1.2 +/- 0.6). CONCLUSION: Long-term low-dose AZM therapy may improve the compromised oropharyngeaL barrier function in patients with CF, opening new perspectives for early treatment of P. aeruginosa infection in CF.

Interim results of a randomized trial of mitomycin C as an adjunct to radical radiotherapy in the treatment of locally advanced squamous-cell carcinoma of the cervix.

The purpose of this study was to determine the efficacy of mitomycin C as an adjunct to radiotherapy for the treatment of locally advanced cervix cancer. Patients with squamous-cell carcinoma of the cervix, stages IB2-IVA, were randomized to receive radiotherapy alone or radiotherapy with concomitant mitomycin C. An initial cohort of 160 patients, having a mean follow-up of 46 months, is analyzed. Intravenous mitomycin C, 15 mg/M(2), was given on the first and sixth week of radiotherapy. The 78 patients in the radiotherapy with mitomycin C group and 82 patients in the radiotherapy alone group have a comparable distribution by age and stage (mean age 47 years; stage IB 3%, IIA 11%, IIB 48%, IIIA 1%, IIIB 36%, IVA 3%). The four-year actuarial survival rates for radiotherapy with mitomycin C and radiotherapy alone were 72% and 56%, respectively (P = 0.13). The four-year actuarial disease-free survival rates for radiotherapy with mitomycin C and radiotherapy alone were 71% and 44%, respectively, a statistically significant difference (P = 0.01). The four-year actuarial local recurrence-free survival rates for patients receiving radiotherapy with mitomycin C and radiotherapy alone were 78% and 63%, respectively (P = 0.11). Differences in four-year distant recurrence-free survival between radiotherapy plus mitomycin C and radiotherapy alone were significantly different at 85% vs. 61% (P = 0.01); this analysis is not adjusted for local failure. On subgroup analysis, stage III-IVA patients had a four-year actuarial disease-free survival of 75% for radiotherapy plus mitomycin C compared with 35% for radiotherapy alone (P = 0.03). There were no treatment- related deaths. Mild hematologic toxicity was seen only in the group treated with mitomycin C. No excess in non-hematologic toxicity has been observed thus far with combined mitomycin C and radiotherapy. In this open phase III trial of mitomycin C as an adjunct to radical radiotherapy for squamous-cell carcinoma of the cervix, there were minimal hematologic effects and no increase in acute radiation reactions. A statistically significant difference in favor of patients receiving mitomycin C is shown for disease-free survival. Thus far, there are trends in favor of those patients receiving mitomycin C for survival and local control. Patients with more advanced stage disease, predominantly stage IIIB, appear to have the most benefit. These preliminary results support the hypothesis that targeting hypoxic cells may lead to a therapeutic enhancement in the radiotherapy of cervix cancer. This trial continues to accrue patients and follow-up data. Int. J. Cancer (Radiat. Oncol. Invest.) 90, 206-223 (2000).

Preparation of red blood cells containing exogenous hemoglobin.

A technique is described for opening the membrane of a red blood cell by electroporation in a manner which permits free exchange of the native hemoglobin with exogenous hemoglobin in the surrounding medium. After resealing the RBC's demonstrate near normal size and hemoglobin content and retain an effective methemoglobin reduction system. This method can be used to introduce natural or genetically engineered hemoglobins with altered oxygen binding characteristics. Allosteric effectors and other non-diffusible small molecules can be encapsulated during the same procedure. A fish Root effect hemoglobin exchanged into rat RBC's produced oxygen transport characteristics, unloading at high pressure at acidic pH, which should be useful to treat tissue hypoxia from a variety of causes.

Chemotherapy as an adjunct to radiation in the treatment of squamous cell carcinoma of the head and neck: results of the Yale Mitomycin Randomized Trials.

PURPOSE: Two consecutive randomized trials were run at our institution using the bioreductive alkylating agent mitomycin as an adjunct to radiation therapy in an effort to improve outcome in patients with squamous cell carcinoma of the head and neck. METHODS: Between 1980 and 1992, two consecutive randomized trials using mitomycin (trial 1) and mitomycin with dicumarol (trial 2) as an adjunct to radiation therapy in patients with squamous cell carcinoma of the head and neck were conducted at our institution. The patients were stratified by intent of therapy, extent of disease, and primary tumor site. Within each strata, patients were randomized to receive radiation therapy with or without mitomycin (trial 1) or mitomycin/dicumarol (trial 2). RESULTS: A total of 203 patients were enrolled onto both trials, 195 of whom were eligible for analysis. Patients were equally balanced with respect to sex, age, extent of disease, primary site, radiation dose, and total duration of radiation treatment. Hematologic toxicities were more frequently noted in the drug-treated arms, but were acceptable with no drug-related treatment deaths. Nonhematologic toxicities were acceptable and not significantly different between the two arms. As of September 1995, with a median follow-up of 138 months, a statistically significant benefit occurred in the mitomycin arms with respect to cause-specific survival (0.74 +/- 0.05 v 0.51 +/- 0.05; P = .005), local recurrence-free survival (0.85 +/- 0.04 v 0.66 +/- 0.05; P = .002), and local regional recurrence-free survival (0.76 +/- 0.05 v 0.54 +/- 0.05; P = .003). No statistically significant difference in overall survival was obtained (0.48 +/- 0.05 mitomycin arms v 0.42 +/- 0.05 radiation alone). CONCLUSION: The bioreductive alkylating agent mitomycin is a safe and effective adjunct to radiation therapy in the treatment of squamous cell carcinoma of the head and neck. The statistically and clinically significant improvement in local regional relapse and cause-specific survival obtained support the use of mitomycin as an adjunct to radiation therapy in the management of squamous cell carcinoma of the head and neck.

Bioreductive alkylating agent porfiromycin in combination with radiation therapy for the management of squamous cell carcinoma of the head and neck.

Porfiromycin (methyl mitomycin C) has been shown in laboratory studies to have increased preferential cytotoxicity to hypoxic cells and therefore may provide enhanced therapeutic efficacy over mitomycin C when used in combination with radiation therapy (RT). The purpose of the two clinical studies reported here is to evaluate the concomitant use of porfiromycin with RT in the management of squamous cell carcinoma of the head and neck. Between October 1989 and July 1992, 21 patients presenting with locally advanced stage III/IV squamous cell carcinoma of the head and neck were entered into a phase I toxicity trial evaluating porfiromycin as an adjunct to RT. Patients were eligible if they had biopsy documented squamous cell carcinoma of the head and neck with a low probability of cure by conventional means. Patients were treated with standard fractionated daily RT to a total median dose of 63 Gy, with porfiromycin administered on days 5 and 47 of the course of RT. Upon completion of this phase I trial, a phase III trial was initiated in November 1992 randomizing patients with squamous cell carcinoma of the head and neck to RT with mitomycin C vs. RT with porfiromycin. There is no radiation only arm in this current trial. To date, 75 patients have been entered on this trial and acute toxicity data are available on 67 patients (34 porfiromycin, 31 mitomycin C) who have completed their entire course of treatment. Median follow-up of the 21 patients enrolled in the phase I porfiromycin trial is 58.5 months. Of the 21 patients, 5 were treated at a dose of 50 mg/M2, 4 at 45 mg/M2, and the final 12 at 40 mg/M2, which appeared to result in acceptable acute hematological and nonhematological toxicities. As of December 1995, 14 of the 21 patients have died with disease and 7 remain alive and free of disease, resulting in a 5-year actuarial survival of 32%. Of the patients enrolled to date in the phase III randomized trial of mitomycin C vs. porfiromycin, there have been no statistically significant differences between the two arms with respect to white blood cell count (WBC), platelet, or hemoglobin nadirs. Acute nonhematological toxicities including mucositis, epidermitis, odynophagia, and nausea have also been comparable. Two patients in this current randomized trial died during treatment, apparently of nondrug-related causes. We conclude that the bioreductive alkylating agent porfiromycin has demonstrated an acceptable toxicity profile to date. Final analysis of the phase I trial, which revealed a 5-year no evidence of disease survival rate of 32% in patients with locally advanced disease and a low probability of cure, appears encouraging. We anticipate completion of the current ongoing trial comparing mitomycin C to porfiromycin in the next 2 years. Further investigations, including large-scale multiinstitutional trials employing bioreductive alkylating agents or other hypoxic cell cytotoxins as adjuncts to RT, are warranted.

Low-dose combined therapy with fluvastatin and cholestyramine in hyperlipidemic patients.

OBJECTIVE: To compare the low-density lipoprotein (LDL) cholesterol-lowering efficacy of low-dose combinations of cholestyramine and fluvastatin. DESIGN: Randomized, double-blind, parallel group, placebo-controlled trial with a 24-week double-blind treatment period divided into three phases. SETTING: Office-based clinics. PATIENTS: Hypercholesterolemic, with LDL cholesterol of 4.14 mmol/L or greater (> or = 160 mg/dL) and plasma triglycerides of 3.39 mmol/L or less (< or = 300 mg/dL). Four hundred sixty patients were screened; 224 patients were randomized into a double-blind treatment period; 203 completed the study; 6 dropped out because of adverse events. INTERVENTION: Patients were treated with 10 mg or 20 mg of fluvastatin alone, 8 g or 16 g of cholestyramine alone, or combinations of these fluvastatin and cholestyramine dosages (six treatment groups). MEASUREMENTS: Changes in lipid variables, particularly LDL cholesterol. RESULTS: The 10-mg and 20-mg fluvastatin monotherapy groups showed considerable reductions in LDL cholesterol initially (-20.1% [SD, 8.8%] and -20.2% [SD, 10.1%], respectively); these reductions were maintained. Reductions in LDL cholesterol that resulted from the addition of cholestyramine, 8 g/d, to 10 mg of fluvastatin and 20 mg of fluvastatin were greater than those observed with monotherapy (10-mg fluvastatin--[10-mg fluvastatin plus cholestyramine], 9.1%; 95% CI, 3.8% to 14.4%) and 20-mg fluvastatin--[20-mg fluvastatin plus cholestyramine], 11.6%; CI, 6.5% to 16.8%). The increase in cholestyramine dose to 16 g/d in the three combination groups provided only a modest additional response. CONCLUSIONS: Low-density lipoprotein cholesterol reductions of about 25% to 30% can be achieved with low-dose combination therapy with fluvastatin and cholestyramine. The addition of low-dose resin appears to produce greater overall cholesterol reduction than does a simple doubling of the fluvastatin dosage. The low-dose combination treatment was highly successful in achieving the goals of the National Cholesterol Education Program guidelines.

Mitomycin C: a prototype bioreductive agent.

Hypoxic cells of solid tumors represent a therapeutically resistant population that limits the curability of many solid tumors by x-irradiation and by most chemotherapeutic agents. The oxygen deficit, however, creates an environment conducive to reductive processes that results in a major exploitable difference between normal and neoplastic tissues. Mitomycin C (MC) can be reductively activated by a number of oxidoreductases, in a process required for the production of its therapeutic effects. This enzymatic reduction results in preferential activation of MC under hypoxia and, in most instances, the production of greater toxicity to oxygen-deficient cells than to their oxygenated counterparts. DNA appears to be the most important target of the reactive species generated from MC, with both mono- and bis-adducts of DNA being formed in drug-treated cells. The demonstration that MC, used to kill the hypoxic fraction, in combination with x-irradiation, to eradicate the oxygenated portion of the tumor, produced enhanced cytodestructive effects on solid tumors of animals has led to the clinical evaluation of the mitomycin antibiotics in combination with x-rays in patients with cancers of the head and neck. The findings from these clinical trials have demonstrated the utility of directing a concerted therapeutic attack on the hypoxic fraction of solid tumors as an approach toward enhancing the curability of localized neoplasms by x-irradiation.

Breast conservation therapy without axillary dissection. A rational treatment strategy in selected patients.

PURPOSE: Patients with early stage breast cancer are being treated with adjuvant systemic therapy with increasing frequency regardless of the pathological status of the axillary lymph nodes. The purpose of this study was to determine the outcome for local regional control in patients treated with radiation therapy to the intact breast and regional lymph nodes without axillary dissection. PATIENTS AND METHODS: The patient population for this study consists of 327 patients with clinical stage I or II invasive breast cancer who were treated by lumpectomy alone without axillary dissection followed by radiation therapy to the intact breast and regional lymph nodes. Outcome for local regional control and survival is reported. RESULTS: As of December 1990, with a median follow-up of more than 10 years, the overall 10-year survival rate was 71%. There were a total of eight regional nodal failures resulting in a 5-year actuarial nodal control rate of 97%. Minimal morbidity was associated with this treatment policy. CONCLUSIONS: For selected patients undergoing breast preservation therapy, lumpectomy alone without axillary dissection followed by radiation therapy to the intact breast and regional lymph nodes results in a high rate of local regional control. Selected patients in whom the results of the axillary lymph node dissection will not influence decisions regarding systemic therapy are candidates for this approach.

Local recurrence versus new primary: clinical analysis of 82 breast relapses and potential applications for genetic fingerprinting.

PURPOSE: The purpose of this study was to perform a detailed clinical pathological analysis of breast relapses in patients treated with conservative surgery and radiation therapy in an effort to classify those relapses as true local recurrences or second primary tumors, and to assess the prognostic and therapeutic implications of such a classification system. METHODS AND MATERIALS: Of 990 patients treated with conservative surgery and radiation therapy at our facilities prior to December 1987, 82 patients have experienced a relapse in the conservatively treated breast as the primary site of failure. Patients were classified as having new primary tumors if they fulfilled any one of the following criteria: a) breast relapse occurring at a site distinctly removed from the original tumor; b) histology of the breast relapse compared with the original tumor consistent with a new primary; or c) DNA flow cytometry converting from an aneuploid primary to a diploid relapse. RESULTS: As of 2/92, with a median follow-up of 5.4 years from the time of breast relapse, the overall 5-year survival rate following breast relapse was 55%. Forty-seven patients were classified as true recurrences and 33 patients were classified as new primaries. Patients classified as true recurrences had a shorter median time to breast relapse than patients classified as new primaries (3.16 years vs. 5.42 years, p < .05) and an inferior post breast recurrence survival rate compared to patients classified as new primaries (36% vs. 89%, p < .05). Residual disease outside of the recurrent tumor bed was also noted to be more frequent in patients classified as true recurrences compared to patients classified as new primaries (48% vs. 16%, p < .05). CONCLUSION: Based on the clinical and pathological criteria outlined, it appears that a significant portion of patients experiencing a relapse in the conservatively treated breast may have new primary tumors as opposed to true local relapses. Distinction between a true recurrence and a new primary tumor may have significant prognostic implications. Uncertainties associated with the clinical and pathological criteria are presented and further investigations with genetic fingerprinting techniques to establish the clonality of breast relapses are presented and discussed.

Mitomycin C as an adjunct to postoperative radiation therapy in squamous cell carcinoma of the head and neck: results from two randomized clinical trials.

PURPOSE: This study was undertaken to assess the benefit of mitomycin C as an adjunct to postoperative radiation therapy in patients with operable squamous cell carcinoma of the head and neck. METHODS AND MATERIALS: Between May 1980 and May 1991, 182 patients have been enrolled in two consecutive randomized clinical trials testing mitomycin C as an adjunct to radiation therapy in squamous cell carcinoma of the head and neck. In both trials, patients were stratified by stage, disease site and intent of therapy. This subset analysis includes 113 patients entered into these two randomized trials treated with surgery and postoperative radiation therapy. In the first trial, patients were randomized to receive standard postoperative radiation therapy alone compared with postoperative radiation therapy with concomitant mitomycin C. In the second trial, patients were randomized to postoperative radiation therapy or postoperative radiation therapy with concomitant mitomycin C plus dicoumarol. RESULTS: As of November 1991, the 113 patients treated with surgery and postoperative radiation therapy in both trials had a median follow-up of 93 months. There have been a total of 12 local recurrences in the radiation therapy alone arm compared to 0 local recurrences in the radiation therapy/mitomycin C arm. There were eight regional recurrences in the radiation therapy alone arm compared with five regional recurrences in the mitomycin C arm. Patients in the mitomycin C arm experienced a superior 5-year actuarial local regional control rate (87% vs. 67%, p < .015) and a statistically significant disease-free survival benefit (67% vs. 44%, p < .03). Overall survival difference between the two arms (56% vs. 41%) has not reached statistical significance. CONCLUSIONS: We conclude from these prospectively designed randomized clinical trials that in patients with operable head and neck cancer treated with surgery and postoperative radiation therapy, concomitant administration of mitomycin C with radiation therapy will result in a statistically significant disease-free survival and local regional control benefit. We are currently investigating the value of other bioreductive alkylating agents as adjuncts to radiation therapy in patients with squamous cell carcinoma of the head and neck.

Preclinical evaluation of Oxygent as an adjunct to radiotherapy.

These studies examine the potential value of a concentrated emulsion of perfluorooctylbromide (perflubron; Oxygent, Alliance Pharmaceutical Corp.) as an adjunct to radiotherapy. The effects of Oxygent on solid tumors were examined using EMT6 mammary tumors in BALB/c mice and BA1112 rhabdomyosarcomas in WAG/rij rats. Treatment with Oxygent plus O2, carbogen (95% O2/5% CO2), or hyperbaric oxygen (HBO) increased the effects of radiation on the tumors. Analyses of tumor cell survival curves and measurements of intratumor pO2 showed that this potentiation reflected an increase in the proportion of well-oxygenated tumor cells. Neither treatment of the animals with carbogen, O2, or HBO alone nor treatment of air-breathing rodents with Oxygent produced changes of similar magnitude. Treatment with a vehicle emulsion containing all the components of Oxygent except the perflubron did not alter tumor radiosensitivity, showing that tumor radiosensitization required the oxygen-transporting perfluorocarbon, and did not result from any biologic or physiologic effects of other components of the emulsion. These studies also examined the effects of Oxygent on the radiation responses of mouse skin and bone marrow. Oxygent selectively increased the radiation sensitivity of tumors relative to these normal tissues, thereby increasing the therapeutic ratio and producing therapeutic gain. Oxygent appears to warrant further testing as an adjunct to cancer therapy.

Fluosol and hyperbaric oxygen as an adjunct to radiation therapy in the treatment of malignant gliomas: a pilot study.

Several clinical trials have been reported using Fluosol and oxygen breathing as an adjunct to radiation. Theoretical considerations and animal experiments, however, indicate that a combination of perfluorochemicals and hyperbaric oxygen (HBO) increases tumor oxygenation and radiation response to a greater extent than is seen either with a perfluorochemical and normobaric oxygen or with HBO alone. This is the first report of a pilot study of the use of Fluosol and HBO with radiation in humans. Twenty patients with anaplastic astrocytoma or glioblastoma multiforme were treated in a phase I trial of radiation with Fluosol and HBO at three atmospheres. Total Fluosol dose was escalated from 42 ml/kg in six courses to 80 ml/kg in four courses. Patients were irradiated in an HBO chamber with 600 cGy weekly fractions following Fluosol administration. Sixteen patients completed treatment; no interruption was necessitated by treatment toxicity. The addition of Fluosol/HBO did not increase the incidence of HBO related toxicities. No significant chronic toxicities were seen. This pilot study demonstrates that Fluosol and HBO can safely be used as an adjunct to radiation in the treatment of human tumors.

Effects of hyperbaric oxygen and a perfluorooctylbromide emulsion on the radiation responses of tumors and normal tissues in rodents.

Perfluorochemical emulsions are being examined in many laboratory and clinical studies as possible adjuncts to radiotherapy and chemotherapy. The studies reported here examine the clinical potential of hyperbaric oxygen (HBO) in combination with a highly concentrated perfluorochemical emulsion (Oxygent) containing 100% w/v perfluorooctylbromide (PFOB). HBO alone produced only a small improvement in the radiation response of BA1112 tumors in WAG/rij rats, while regimens combining HBO with Oxygent produced much greater radiation sensitization. A sham emulsion, formulated without the O2-carrying PFOB, did not alter the radiation response of the tumors in comparison with that seen with HBO alone. Neither HBO nor Oxygent plus HBO altered the radiosensitivity of bone marrow progenitor cells in BALB/c mice. HBO alone augmented skin reactions in BALB/c mice, but addition of Oxygent did not alter the skin reactions in comparison to those seen with HBO alone. Regimens combining Oxygent with HBO selectively increased the radiation sensitivity of tumors relative to normal tissues, thereby enhancing the therapeutic ratio. These results support the potential usefulness of perfluorochemical emulsions and HBO in clinical radiation therapy.

A simple technique for irradiation of recto-anal cancers with electrons using an internal anal shield.

A method of treating the primary site of recto-anal cancers using an en face electron beam in combination with an internal lead shield in the anus has been developed. Dose measurements using lithium fluoride thermoluminescent dosimetry indicate that the internal anal shield reduces the dose to the uninvolved anal wall by up to a factor of two while leaving the dose to the primary tumor site unaffected. Because the internal anal shield is placed in the anus during treatment, this system leads to a more precise daily positioning of the shield compared to the setup using an external shield alone. This technique has been used to treat two patients with anal cancer who tolerated the treatment well with no acute side effects. Both patients are now disease free, more than 30 months after their radiation treatment, without any treatment-related sequelae.

Modulation of tumor oxygenation and radiosensitivity by a perfluorooctylbromide emulsion.

The effect of a concentrated perfluorooctylbromide emulsion (Oxygent) on the radiosensitivity and oxygenation of solid tumors was examined using EMT6 mammary tumors in BALB/c mice and BA1112 rhabdomyosarcomas in WAG/rij rats. Treatment with Oxygent plus carbogen or oxygen breathing increased the radiosensitivity of both tumors. Analysis of tumor cell survival data and polarographic measurements of intratumoral pO2 indicated that this potentiation reflected an increase in the proportion of well-oxygenated tumor cells. Treatments with carbogen breathing alone, with Oxygent plus air-breathing, or with a vehicle emulsion containing all the components except the perfluorocarbon did not produce comparable improvements in tumor radiosensitivity. Concentrated perfluorooctylbromide emulsions appear to warrant further development and preclinical testing as adjuncts to cancer therapy.

Pathologic stage I and II Hodgkin's disease. Long-term results at three Connecticut hospitals.

Three radiation therapy departments in Connecticut (Uncas on Thames Hospital, Norwich; Yale-New Haven Hospital, New Haven; and the Hospital of Saint Raphael, New Haven) have consistently used the strategy of staging laparotomy with splenectomy for clinical stage I and II Hodgkin's disease patients with primary radiation therapy as initial therapy for most pathologic stage (PS) I and II patients. From 1971 through 1986, 239 PS I and II patients were treated at these three institutions and 94% received radiation therapy alone as initial treatment. With a minimum follow-up time of one year and a maximum follow-up time of 18 years (mean: 7.3 years), only 19 (8%) of the 239 patients have ultimately died of Hodgkin's disease. Two factors were responsible for the low death rate due to Hodgkin's disease: 1) 176 patients (74%) went into complete remission following initial therapy and did not experience a relapse; and 2) 63 patients relapsed following initial therapy; however, subsequent salvage therapy was successful in 44 (70%) of these 63 patients. The overall 10-year and 18-year survival rates were 81% and 78%, respectively. Staging laparotomy with initial radiation therapy for most PS I and II patients remains an important and highly successful strategy for Hodgkin's disease.

Regional nodal irradiation in the conservative treatment of breast cancer.

At this institution conservative treatment of breast cancer was begun in the 1960's. The following analysis represents our experience through 1984 with specific reference to the management of the regional lymph nodes. A total of 432 patients with clinical stage I and II breast cancer were treated between 1962 and 1984 with lumpectomy and radiation therapy. The breast was treated with tangential fields to a median dose of 4800 cGy and electron conedown to a total tumor bed dose of 6400 cGy. Axillary dissection was not routinely performed, particularly in the earlier years. More recently, axillary dissection has been used with increasing frequency if it was felt that the results of the dissection would influence systemic treatment. One hundred eighty-seven patients (43%) underwent axillary dissection (30% pathologically positive) and routinely received regional nodal irradiation (median dose 4600 cGy) to the internal mammary and supraclavicular lymph nodes. Two hundred forty-five patients (57%) did not undergo axillary dissection and routinely received regional nodal irradiation to the internal mammary, supraclavicular, and entire axillary regions to a total median dose of 4600 cGy. As of May 1989 with a median follow-up of 7.5 years, there have been a total of 12 nodal failures for an actuarial nodal control rate of 97% at 5 years and 96% at 10 years. The actuarial 5-year regional nodal control rate was the same for both the group of patients receiving regional RT alone without axillary dissection and the group of patients receiving axillary dissection and supraclavicular/internal mammary radiation. There has been minimal morbidity associated with this treatment policy. We conclude that regional nodal irradiation as described above, with or without axillary dissection, results in a high rate of regional nodal control and minimal treatment morbidity in patients undergoing conservative treatment of early stage breast cancer.

Rocky Mountain spotted fever. When and why to consider the diagnosis.

Rocky Mountain spotted fever, caused by a rickettsial organism transmitted by the bite of a tick, can be confused with many more common diseases. Diagnosis is made more challenging by the fact that treatment is most efficacious if begun before the second week of illness. Tetracycline and doxycycline are the most successful therapeutic agents against this potentially fatal disease.

Pulmonary function and symptoms after inhalation of endotoxin.

In previous experiments, a good relationship was demonstrated between the amount of airborne bacterial endotoxin and acute reactions after exposure to organic dusts. In the present study, 77 naive subjects were exposed to isolated endotoxin (IE) or endotoxin attached to bacterial cells (CE). Both preparations were obtained from Enterobacter agglomerans, which is a major bacterial species in many organic dusts. The major physiologic effect caused was a dose-related decrease in transfer factor, as measured by carbon monoxide diffusion. Half of the subjects reported fever and about one-third a subjective feeling of chest tightness. The exposure also caused a dose-related but small decrease in FEV1. A slightly increased bronchial reactivity was demonstrated at 4 h after endotoxin exposure. The minute volume after CO2 exposure was marginally affected. The results further support the conclusions from epidemiologic and experimental studies that the bacterial endotoxin is responsible for the acute reactions seen after exposure to many organic dusts, including that derived from cotton.

Randomized clinical trial of mitomycin C as an adjunct to radiotherapy in head and neck cancer.

A randomized prospective clinical trial was carried out to assess the usefulness of the addition of mitomycin C to radiation therapy used alone or in combination with surgery for the treatment of squamous cell carcinoma of the head and neck region. One hundred and twenty patients with biopsy proven tumor of the oral cavity, oropharynx, larynx, hypopharynx, and nasopharynx were randomly assigned to receive or not receive mitomycin C; all other aspects were similar in the two treatment groups. One hundred and seventeen patients were evaluable with a median follow-up time of greater than 5 years. Acute and chronic normal tissue radiation reactions were equivalent in the two treatment groups. Hematologic and pulmonary toxicity were observed in the drug treated patients. Actuarial disease-free survival at 5 years was 49% in the radiation therapy group and 75% in the radiation therapy plus mitomycin C group, p less than 0.07. Local recurrence-free survival was 66% in the radiation therapy group and 87% in the radiation therapy plus mitomycin C group, p less than 0.02. The findings demonstrate that mitomycin C can be administered safely as an adjunct to radiation therapy in the treatment of head and neck cancer. The drug improves local tumor control without enhancing normal tissue radiation reactions.