Biomedical subjects
Publications and source records attributed to D H Johnson.
Glaucoma is a potentially blinding ocular disease that commonly affects elderly persons. In this review, we discuss the range of clinical findings, appropriate diagnostic tests, and available medical, laser, and surgical treatment options. New developments in the evaluation of the optic nerve and in visual field testing may facilitate the early detection of glaucoma, and new therapeutic agents hold promise for the future.
Small cell lung cancer is a common, usually fatal neoplasm. Although palliative therapy is available for the majority of patients, only a very small minority enjoy long-term survival. Ironically, this neoplasm is nearly entirely preventable and a successful antismoking program is desperately needed. Our efforts to understand the basic biology of this tumor should continue, and, hopefully, will eventually translate into improvements in therapy. In addition to following the leads provided by basic research, a concerted clinical research effort needs to continue to build upon the advances already achieved.
Review of clinical data from 350 patients with small-cell lung cancer (SCLC) revealed hyponatremia (sodium less than 130 mEq/L) attributable to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) in 40 patients (11%). Although hyponatremia was severe in most instances (median, sodium 117 mEq/L), symptoms attributable to water intoxication were identified in only 27% of hyponatremic episodes. Development of SIADH showed no correlation with clinical stage, distribution of metastatic sites, sex, or histologic subtype of small-cell carcinoma. SIADH occurred most often with initial presentation (33 of 40), and resolved promptly (less than 3 weeks) with initiation of combination chemotherapy in 80% of evaluable patients. The presence of SIADH did not influence response to chemotherapy or overall survival as an independent variable. However, in five patients profound hyponatremia developed immediately following primary cytotoxic therapy (range, one to five days). Despite initial control of SIADH, dilutional hyponatremia recurred in 70% of patients with tumor progression. Our findings suggest that development of clinically demonstrable SIADH in patients with SCLC is dependent on functional properties of the neoplastic cells, rather than tumor burden or metastatic site. The potential for development of clinically significant hyponatremia early in the course of cytotoxic therapy emphasizes the need to closely monitor patients, particularly those receiving chemotherapy regimens requiring substantial intravenous hydration.
Four patients with germ-cell tumors of the testis had acute vascular ischemic events after treatment with cisplatin-based combination chemotherapy. Two patients had myocardial infarctions and two others cerebrovascular accidents. All patients were less than 30 years old and had no significant risk factors for atherosclerotic cardiovascular disease. Angiographic studies done in three patients showed no endovascular abnormalities. Raynaud's phenomenon preceded acute myocardial infarction in one patient with angiographic evidence of ergonovine-induced coronary artery spasm. We suggest that major arterial occlusive events may occur as a result of treatment with cisplatin-based combination chemotherapy.
Small-cell lung cancer is rarely cured with standard chemotherapy, despite initial good responses. The concept of high-dose induction therapy for extensive-stage patients has been explained in a series of pilot studies. The rationale of this approach and the most recent preliminary results will be presented.
Ninety-two patients with advanced non-small cell lung cancer were treated with a combination chemotherapy regimen containing cisplatin, vindesine, and etoposide. Eighteen patients (20%) achieved major responses to therapy (three complete responders and 15 partial responders). Response rates were similar in each histologic subtype. Initial performance status was an important determinant of response; 42% of the patients with a Karnofsky performance status greater than or equal to 70% responded versus 5% of those with a performance status less than 50%. The median duration of partial response was 21 weeks; complete responders had a median response duration of 50 weeks. The median survival for the entire group was 23.5 weeks. Toxicity with this regimen was acceptable; myelosuppression was the major toxic effect and was severe in only 10% of the patients. This regimen produced response rates comparable to those reported with other combinations containing cisplatin. Survival advantage in patients receiving this treatment is not established.
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Three patients with widely disseminated Merkel cell tumors of the skin are presented. In all three cases, neuron-specific enolase (NSE) was demonstrated in neoplastic tissue by immunohistochemical staining, and serum NSE levels were also elevated in all three patients. Serum NSE may prove to be a useful tumor marker in this and other malignancies of neuroendocrine origin.
Inflammatory breast cancer is a distinct clinicopathologic entity that accounts for 1 percent of all cases of breast cancer. The diagnosis should be strongly suspected on the basis of the distinctive clinical findings, which include edema of the breast, inflammation, wheals, and a typical reddish-purple color of the overlying skin. Pathologic examination usually shows infiltration of the dermal lymphatics with carcinoma. Evidence of distant metastatic spread is more frequent than with other types of breast cancer and is seen in approximately 30 percent of patients. The five-year disease-free survival rate is less than 5 percent when local therapy alone (mastectomy and/or local radiotherapy) is used. The addition of combination chemotherapy to high-dose local radiotherapy has improved the five-year survival rate to approximately 30 percent. The potential for long-term survival is limited to the subgroup of patients with only local-regional disease at the time of diagnosis. Patients with inflammatory breast cancer should be treated with combined-modality therapy using combination chemotherapy and high-dose radiotherapy to the breast, since this approach is potentially curative. The fatalism formerly associated with this diagnosis is no longer warranted, particularly in patients with local-regional disease. Failure to employ intensive combined-modality treatment will deny some patients a chance for long-term survival.
False aneurysm of the aorta developed in a 14-month-old child following endoscopic removal of an open safety pin from the esophagus. The diagnostic techniques and operative repair of this rare complication of foreign body ingestion are described.
Eighty-five subjects were tested for the presence of circulating candidal antigen (CAg) and anti-candidal antibody (CAb) using both an enzyme immunoassay (ELISA) and counterimmunoelectrophoresis (CIE). The 72 studied controls included laboratory volunteers; hospitalized patients without evidence of infection; febrile hospitalized patients without evidence of candidiasis; and patients with superficial candidiasis and candiduria. The control subjects were compared with 13 patients with proven disseminated candidal infection (disease prevalence = 15%). The ELISA CAb test was of greater individual sensitivity (92%) in separating patients with systemic candidiasis from all controls combined than the ELISA CAg, CIE CAg, or CIE CAb test (61%, 15%, 69%, respectively). The CIE CAg test, though specific (100%), was insensitive. Sensitivity, specificity, and predictive values were generally enhanced by employing combinations of tests. Sera from patients with disseminated candidiasis were much more likely to yield a positive result by two or more serologic tests than were control sera (p = less than 0.0004). The sensitivity of combinations ranged from 15% to 92%. The specificity of combinations ranged from 21% to 100%. The predictive value positive of combinations test ranged from 40% to 100%. Predictive value negative of combinations ranged from 69% to 98%. Patients with a variety of superficial and deep candidal infections apparently have detectable circulating CAb and/or CAg. The ELISA CAb test was superior to the other tests in identifying patients with disseminated candidiasis. Combinations of serologic tests may be superior to individual tests in the diagnosis or exclusion of serious disease due to Candida albicans.
Discharges were recorded extracellularly from single units localized in the lateral superior olive (LSO) of barbiturate anesthetized cats. The statistical properties of the unit discharges to monaurally presented tone bursts were determined. Increasing the stimulus level of an ipsilaterally presented tone burst produced an increase in the discharge rate and the emergence and growth of a time-locked discharge pattern in the initial portion of the response. The initial time-locked response was transient and was followed by a nontime-locked sustained response. In the sustained portion, increasing stimulus level produced increases in rate and changes in the interspike interval statistics. Average rate and interval statistics were found to be systematically related. LSO units were differentiated on the basis of rate and pattern of their initial discharges into two main types: the fast and slow chopping units. An analysis of the results indicated that some aspects of response type differences may be related to input characteristics rather than to neuron response mechanisms.
A standardized cardiovascular risk factor examination was given to executives in the headquarters of the American Telephone and Telegraph Company and the Nippon Telegraph and Telephone Public Corporation. As expected from the national mortality data, evidence of ischaemic heart disease was more common among American than Japanese executives. The frequency of some but not all risk factors was consistent with the observed differences in ischaemic heart disease. Americans were fatter than their Japanese counterparts, obtained a higher proportion of their caloric intake from animal fats, had higher serum cholesterol levels, and more of them felt that their lives were highly stressful. On the other hand, Japanese executives were much more likely to be cigarette smokers and showed a greater increase in blood pressure with age. Serum high-density lipoprotein cholesterol levels and the ratio of saturated to unsaturated fatty acids in the serum were similar in the two groups.
Seventeen ambulatory patients with extensive-stage small-cell lung cancer received one or two courses of high-dose induction chemotherapy consisting of cyclophosphamide (100 mg/kg) plus etopside (1,200 mg/m2) followed by four or five cycles of conventional-dose cyclophosphamide (1,000 mg/m2), doxorubicin (40 mg/m2), and vincristine (1.4 mg/m2) (CAV) given every 21 days. No additional chemotherapy was given until relapse or progression was documented. Response was assessed initially after high-dose induction therapy and again after completion of all chemotherapy. After induction therapy, 16/17 (94%) patients had achieved an objective response, including five (29%) complete responses and 11 (65%) partial responses. Two partially responding patients improved to a complete response after CAV, while one partial responder progressed and one patient died of an intercurrent illness while receiving CAV. Thus, the overall response after completing all chemotherapy was 15/16 (94%), including seven (44%) complete responses and eight (50%) partial responses. Median response duration was six months (range, 3 to 11 months), and overall median survival was ten months (range, 2 to 17 months). All 31 courses of induction therapy were associated with leukopenia (less than 1,000/microL), 81% with thrombocytopenia (less than 20,000/microL), and 77% with fever (greater than 38.5 degrees C). Seven episodes of bacteremia and one axillary abscess were documented, and there was one treatment-related death (6%). These toxicities are similar to that produced by high-dose etoposide alone. High-dose cyclophosphamide combined with high-dose etoposide can be administered to ambulatory patients with extensive-stage small-cell lung cancer without requiring bone marrow transplantation to reestablish hematopoiesis. Complete response and median survival rates, however, are similar to those obtained with less intensive therapy.
Twelve patients with small-cell lung cancer seen during a 30-month period had jaundice at diagnosis. Five patients had a pancreatic metastasis resulting in extrahepatic biliary obstruction, and seven had diffuse hepatic metastases without extrahepatic obstruction. All patients with pancreatic masses had complete (or nearly complete) resolution of jaundice and abdominal pain within 3 weeks of starting chemotherapy. Patients with extensive liver metastases usually remained icteric in spite of intensive treatment. Three patients with pancreatic metastases survived more than 12 months after the institution of therapy. No patient presenting with jaundice caused solely by hepatic metastases survived beyond 8 months. Small-cell lung cancer can present with jaundice due to diffuse hepatic parenchymal involvement, which is associated with a poor prognosis, or as a result of extrahepatic biliary obstruction, which has potential for rapid palliation and prolonged survival.
Etoposide (VP-16) is one of the most active drugs against small-cell lung cancer. There may be a steep dose-response relationship, and we have explored the use of etoposide as a single agent in a high dose (1,200 mg/m2) without bone marrow transplantation, for patients with very bulky, extensive-stage disease. This therapy is well tolerated in patients having good performance status, with myelosuppression representing the major toxicity. Our data suggest there may truly be a steep dose-response relationship. We have continued to explore intensive induction therapy for selected very poor-prognosis patients by adding high-dose cyclophosphamide (100 mg/kg) to high-dose etoposide. This combination is also very myelotoxic, but quite similar to etoposide alone. Our current study adds cisplatin (120 mg/m2) to the high-dose cyclophosphamide-etoposide schedule in an attempt to take advantage of the synergism seen with these drugs in various other circumstances. This series of studies will give us information regarding the feasibility of intensive induction therapy and provide data for the design of phase III studies.
Twenty-nine patients with refractory recurrent small cell carcinoma of the lung were treated with cisplatin (40 mg/m2) and etoposide (200 mg/m2) each day for 3 days, repeated every 3-4 weeks. Fifteen of these patients had received etoposide in their original treatment regimen. Fifteen (52%) of all patients had a major response, as did nine (60%) of the patients with prior exposure to etoposide. Myelotoxicity was moderately severe. The median duration of responses was 3 months (range, 6-36 weeks). This study suggests synergism between cisplatin and etoposide. The toxicity seen in this heavily pretreated group of patients suggests that smaller doses be studied in this group. The synergism may be best utilized in the initial regimens against small cell lung cancer.
Combination chemotherapy has become the cornerstone of management for patients with small-cell lung cancer. Although the majority of patients are palliated, most continue to die of their disease. Studies designed to improve treatment results and to understand the basic biology of this neoplasm are continuing. Several strategies are now being investigated, including the use of non-cross-resistant chemotherapy, dose intensification, manipulation of the duration of therapy, combined modality therapy, and salvage chemotherapy. Studies in these areas have not yet yielded results that have definitively improved response rates or survival. It appears that further therapy after remission induction has not yet proven beneficial. This paper will review selected areas of therapeutic investigation.