Byron E. Fossieck

The clinical behavior of 'mixed' small cell/large cell bronchogenic carcinoma compared to 'pure' small cell subtypes

Biopsy specimens from 19 previously untreated lung cancer patients were prospectively diagnosed as small cell carcinoma with a large cell component. The patients were thoroughly staged and received intensive combination chemotherapy. They represented 12% of all small cell carcinoma cases eligible for aggressive chemotherapy protocols during a 5.5 year period. To determine whether the clinical behavior of this ‘mixed’ histologic variant differed from the other histologic subtypes of small cell lung cancer, we compared these 19 patients to a concurrent group of 103 patients with only small cell cancer in their diagnostic biopsies given equivalent therapy. The ‘mixed’ histology patients were comparable to the ‘pure’ small cell group in age, performance status, extent of disease, and frequency of bone marrow, liver, bone, and central nervous system metastases. Their complete plus partial response rate (58%) was significantly less than the response rate for the ‘pure’ small cell patients (91%), their complete response rate was also lower (16 versus 46%), and their overall survival was significantly shorter (median, 6 versus 10.5 months). Mixed histology small cell/large cell carcinoma represents a distinct pathologic variant of small cell carcinoma of the lung, associated with lower response rates and shorter survival than the ‘pure’ small cell subtypes. Since combination chemotherapy yields some complete responses and long‐term disease‐free survival in these patients, however, aggressive treatment with potentially curative intent should be considered in their management.

Safety and efficacy of continuous intravenous morphine for severe cancer pain

To study the efficacy and safety of continuously administered intravenous morphine for cancer pain unrelieved by standard narcotic therapy, bolus intravenous injections of 2 to 5 mg of morphine were given every 10 minutes until pain relief was achieved. Within the next hour, continuous intravenous morphine infusion was begun with the hourly dose equal to the cumulative bolus dose. Respiratory rate, pulse, blood pressure, arterial blood gas values, mental status, and pain relief were recorded at baseline and during the study period. A reduction in arterial oxygen pressure (PaO2) and/or increase in arterial carbon dioxide pressure PaCO2 of more than 20 percent of baseline values occurred, during the first 24 hours of infusion, in a minority of patients. This did not require changes in hourly morphine dose. Despite subsequent increases in morphine dose, blood gas values tended to remain at or return toward baseline values. Severe toxicity occurred during one trial and was heralded by bradypnea and marked somnolence. Major pain relief was achieved in 11 of 15 trials. Therefore, continuous intravenous morphine is effective and safe therapy. Bradypnea associated with marked somnolence is a cause for dose reduction.

Bacteremia due to gram-positive cocci in patients with neoplastic disease

Abstract Fifty-seven bacteremias caused by gram-positive cocci were observed over a four and a half year period in patients with a wide variety of malignant diseases. All patients had two or more positive antemortem blood cultures with the same microorganism. The number of bacteremic episodes were divided between Streptococcus pneumoniae (14), other streptococci (17) and Staphylococcus aureus (26). Seventy per cent, including 50 per cent of the pneumococcal bacteremias, were nosocomial. An identifiable portal of bacterial entry in the skin or the gastrointestinal or respiratory tract mucosa was present in 95 per cent, fever in 81 per cent and a prebacteremic performance status of less than 2 in 53 per cent. Granulocytopenia was present in only 18 per cent of the cases at the onset of the bacteremia. These bacteremias appeared to be responsive to antimicrobial therapy with an over-all immediate mortality rate of 23 per cent; 16 per cent in adequately treated patients. Poor outcome was associated with a prebacteremic performance status of 3 or 4, other than optimal antimicrobial therapy, a neutrophil count of less than 1,000/mm 3 at the onset of the infection, and bacteremia due to Strep, pneumoniae. Hospitalized cancer patients, especially those with a poor performance status, should be monitored closely for breaks in the mucocutaneous host defense barriers and, if these are present in the face of suspected systemic infection, initial antimicrobial therapy should include drugs appropriate for the treatment of gram-positive coccal microorganisms.

Septicemic complications of the cutaneous T-cell lymphomas.

The records of 60 consecutive patients with cutaneous T-cell lymphomas were reviewed to determine the incidence, etiology, predisposing factors, therapy, complications and outcome of septicemia. Fourteen (23 percent) patients had 26 septicemias: due to gram-positive cocci in 21 and to gram-negative bacilli in five. The presence of stage IV lymphomatous disease (p 0.032), generalized erythroderma (p less than 0.001), palpable lymph nodes (p 0.014), and histologic involvement of lymph nodes (p 0.023) and peripheral blood (p less than 0.001) identified a subset of patients at high risk for sepsis. Sepsis was correlated with locally infected sites in 77 percent of the episodes. Single antimicrobial therapy was successful in all septicemias due to gram-positive cocci but was accompanied by five secondary gram-negative bacillary superinfections (80 percent fatal). The subsequent mortality in all patients who survived infection (50 percent) indicated their poor over-all prognosis.

Intravenous Followed by Oral Antimicrobial Therapy for Staphylococcal Endocarditis

We have treated 35 cases of staphylococcal endocarditis in 33 patients with intravenous followed by oral antimicrobial therapy. All patients had three or more blood cultures positive for Staphylococcus aureus, and all had cardiac murmurs characteristic of valvular insufficiency. The mean total duration of antimicrobial therapy was 42.4 d, consisting of a mean of 16.4 d of intravenous therapy followed by a mean of 26 d of oral therapy. Intravenous antimicrobial therapy included sodium nafcillin (32 cases; mean dose 9.2 g daily) and clindamycin (three cases). Oral therapy included dicloxacillin or oxacillin (30 cases; mean dose 4.5 g daily), clindamycin (four cases), and potassium penicillin V (one case). Serum bactericidal titers using the blood culture isolates showed similar activity with both intravenous and oral drugs. All patients treated with this sequential intravenous and oral regimen were cured. A regimen of initial intravenous followed by oral antimicrobial therapy, monitored with serum antibacterial activity studies, is a safe, effective, well-tolerated, and economical treatment for staphylococcal endocarditis.

Neurotoxicity during intravenous infusion of penicillin. A review.

Early in its clinical use and again in recent years, reports appeared stressing the direct neurotoxic potential of this agent. Neurotoxic manifestations in both man and animals have been observed after direct application to the cerebral cortex,2 following injection intracerebrally,3-6 after installation into the frontal sinuses,7 and where high cerebrospinal fluid concentrations have been achieved by inj ection intraventricularly,8 intracisternally,940 or into the lumbar subarachnoid space.11-’4 During the past decade, similar toxic effects have been observed in many clinical settings with intravenous administration of varying doses to patients with impairment of renal function7’15-27 and those undergoing cardiopulmonary bypass.23’28-31

Effect of oral prophylactic broad spectrum nonabsorbable antibiotics on the gastrointestinal absorption of nutrients and methotrexate in small cell bronchogenic carcinoma patients

Patients with small cell bronchogenic carcinoma, in a study utilizing laminar‐air‐flow‐protected environments, oral prophylactic broad spectrum non‐absorbable antibiotics (PNAA), and intensive combination chemotherapy, were examined to determine the effects of PNAA on serum biochemical values and on gastrointestinal absorption of both nutrients and methotrexate. With use of PNAA the following abnormalities were observed; serum carotene and folate decreased, D‐xylose absorption was impaired, fat globules and muscle fibers were demonstrable in the stool, and the mean weight loss in 6 weeks was 10.2% as compared with 4.3% in patients not treated with antibiotics. Methotrexate absorption decreased from a mean of 69% prior to antibiotic use to 44% on PNAA. Thus, PNAA causes malabsorption of both nutrients and drugs. It appears unwise to treat patients on PNAA with oral antineoplastic drugs. Nutritional status must also be closely monitored and supplemental nutrition, either intravenously or with elemental diets, must be considered.

Delayed hypersensitivity skin testing as a prognostic indicator in patients with small cell lung cancer

The prognostic importance of pretreatment delayed hypersensitivity skin test reactivity was determined in 154 newly diagnosed, carefully staged and agressively treated small cell lung cancer patients. One hundred twenty‐one patients were reactive to at least 1 of 5 skin test antigens and 33 were anergic. Skin test reactive patients survived significantly longer than anergic patients. This result was expected since there was a significant trend for reactive patients to have good performance status (P = 0.005) and low tumor burden (P = 0.005) compared to anergic patients. The principal finding of this study was that skin test reactivity was of prognostic utility primarily in otherwise good prognosis patients, i,e., individuals with good performance status and low tumor burden. In this group anergy was associated with significantly shortened survival (P = 0.025). In poor prognosis (poor performance status and high tumor burden) or intermediate prognosis (either poor performance status or high tumor burden) patients skin test reactivity or anergy had no significant influence on survival.

Herpes zoster and small cell bronchogenic carcinoma

In nine of 74 (12 per cent) consecutive, previously untreated patients with small cell bronchogenic carcinoma receiving combination chemotherapy herpes zoster developed. This is the highest frequenzy reported for this viral infection in patients with nonlymphoproliferative solid tumors. Cutaneous dissemination developed in six of the nine patients, but visceral involvement did not occur. The major difference between the patients with herpes zoster and those without was the superior duration of median survival for the infected patients. No relationship could be established between the development of herpes zoster and the extent of neoplastic disease, prior radiotherapy, treatment with specific chemotherapeutic agents or corticosteroids, cutaneous anergy or granulocytopenia. Serum specimens obtained from six of the nine patients prior to their infection demonstrated the preexistence of varicella zoster antibodies. As more effective and intensive chemotherapy prolongs the survival of patients with solid tumors, it is possible that the frequency of herpes zoster infection may approach that observed in patients with lymphoproliferative malignancies.

Nafcillin Entry into Human Cerebrospinal Fluid

The entry of nafcillin into the cerebrospinal fluid (CSF) of humans was studied in the absence of meningeal inflammation. Twenty studies were performed in 18 patients receiving 40 mg of sodium nafcillin per kg intravenously over 30 min. The CSF specimens were obtained at 1, 2, 3, and 4 h postinfusion, and sera were obtained at 5 min and 1, 2, 3, and 4 h. Nafcillin was uniformly detected in the lumbar CSF at 1 h, peaked at 2 h postinfusion, and was still detectable in the CSF of three of four patients studied at 4 h.