The partial isolation and characterization of ilotropin, a novel islet-specific growth factor.

In this series of studies, we have presented evidence for a novel, pancreatic islet-specific growth factor, which we call ilotropin. Ilotropin is acid stable, heat stable, ethanol-precipitable, and sensitive to trypsin digestion. It appears to have a molecular weight between 29 - 44,000, and preliminary data not presented here suggests that it has a relatively basic pI. Unlike many other growth factors, ilotropin does not bind to heparin. Ilotropin is distinguishable from most of the known growth factors on the basis of at least one of the characteristics established in these studies. The apparent molecular weight of 29 - 44,000 eliminates all but the larger growth factors such as PDGF and hepatic growth factor. The fact that ilotropin is acid stable rules out identity with hepatic growth factor, and its lack of binding to heparin and apparent basic pI rules out identity with PDGF. Thus, the combination of characteristics described in these studies eliminates most of the known growth factors as candidates for the role of ilotropin. Certain growth factor precursor molecules (e.g. TGF-a) and several interleukins and cytokines (e.g. pro-IL-1 and melanocyte growth factor) also fall into this molecular weight range. Whether these proteins might be related to ilotropin or play a role in its biological activity remains to be determined. Current studies of ilotropin include further purification to homogeneity, determination of the peptide sequence of ilotropin, and development of an in vitro bioassay using trophic responses of primary cultures of pancreatic duct cells as an indicator of ilotropin activity. With purified material we ought to be able to identify the cells of origin and the target cells for the action of ilotropin, and establish assays to determine the relationship to failure of beta-cell regeneration that accompanies diabetes. Ultimately we hope that ilotropin may lead to new ways of approaching aspects of the problems presented in pancreatic beta-cell failure.


Studies of composite grafts of fetal pancreas (FP) and fetal liver (FL) in the streptozotocin-induced diabetic rat.

A hepatotrophic effect of pancreatic islets on co-transplanted hepatocytes has been described recently by Ricordi et al. We investigated a possible reciprocal effect of co-transplanted fetal liver (FL) on fetal pancreas (FP) isografted into streptozotocin diabetic rats. FL was co-transplanted with FP in three sites: the new intramural small bowel (ISB) site, the conventional renal subcapsular (RSC) site, and the historically inhospitable intramuscular (IM) site. Overall, as compared to grafts of FP alone, composite FP/FL grafts consistently provided earlier restoration of normoglycemia in streptozotocin diabetic recipients (24 +/- 8 vs. 67 +/- 43 days P = 0.001). The proportion of recipients rendered normoglycemic and the clearance of glucose was site-dependent. For FP and FP/FL recipients respectively, the ISB site resulted in 100% normoglycemia in both groups (19/19 and 6/6), the RSC site resulted in 71% (5/7) and 40% (2/5) and the IM site resulted in 14% (1/7) and 67% (6/9). In normoglycemic recipients, glucose clearance was normal or supraphysiologic except for the RSC site. Composite isografts brought about normoglycemia in 75% (6/8) of recipients treated with beta-cell toxic doses of cyclosporine that prevented reversal of diabetes in recipients of FP alone. Co-transplantation of FL benefits FP through paracrine mechanisms mediated by unknown factor(s). Thus, as compared to grafts of FP alone, composite FP/FL grafts established normoglycemia more rapidly, mitigated cyclosporine toxicity and corrected diabetes when transplanted in the small bowel site. There are several mediators that may be responsible for these paracrine effects between the liver cells and the pancreas. IGF-1 elaborated by FL is the most likely trophic factor.(ABSTRACT TRUNCATED AT 250 WORDS)


The effects of IGF-I and IGF-II on cell growth and differentiation in the central nervous system.

Both IGF-I and IGF-II peptides have been localized to specific brain regions. The distribution of IGF-I is homogeneous whereas IGF-II appears to be more local. Two species of IGF receptors are found in the CNS. The type II (m6P) is similar to that in the periphery, but the type I has nearly the same affinity for IGF-I and IGF-II. IGF-I has now been shown to provide cell growth and survival as well as stimulate neurite outgrowth. Dorsal root ganglia and sympathetic neurons are sensitive to IGF-II and the action may be additive with NGF. Cells other than neurites, such as oligodendrocytes respond to the IGFs as well as primary and transformed lines. The mechanism of action has not been resolved but IDG-II appears to act via G-protein coupled activation of protein kinase C. Interaction between various growth factors and the IGFs may be due to up or down-regulation of the receptor predicated by the non-homologous peptide.


Islet beta-cell regeneration and reg genes.

In this paper, we show that the reg gene is expressed in experimentally induced regenerating or hyperplastic islets. We have previously reported that ectopic expression of the reg gene occurs in some human colonic and rectal tumors, suggesting that enhanced reg expression may be related to the proliferative state of tumor cells. Reg protein has also been shown to have significant sequence homology with plant and animal lectins, a class of compounds that has been shown to be a growth promoter. At present, any direct relationship between reg protein and beta-cell replication remains to be established. However, since the reg protein is a secretory protein and reg can be expressed at an early stage of pancreatic cell differentiation, the reg protein may act on the stem cells of beta-cells in an autocrine or paracrine manner. In normal mature exocrine cells, the reg gene is expressed and the gene product may be necessary to maintain adequate exocrine pancreatic function. The physiological reasons for the maintenance of two functional reg genes encoding proteins of slightly different sequence in mice are still unclear. The cloning of additional rat and human non-allelic reg genes could provide additional clues.


Regeneration of pancreatic endocrine cells in interferon-gamma transgenic mice.

We have shown that the pancreatic duct cells of IFN-gamma mouse are actively multiplying and that many duct cells differentiate to become endocrine cells. This islet regenerating process closely parallels the islet development during normal organogenesis in the fetus and offers a model for studying the cell lineage relationships of islet cells. The subject has received wide interest and intensive research in recent years. One of the noteworthy results of this study is the finding that duct cells retain the ability to proliferate and to differentiate into islet cells. Under normal conditions, duct cells do not continue to multiply or to differentiate. The results suggest that in the transgenic mice, the progenitor cells of embryonic multipotential duct cells transform into adult cells, but in the presence of appropriate signals or stimuli can resume their multipotential property. The appearance of hepatocytes indicates that while the cell proliferation observed largely results in endocrine cells, other differentiation pathways are occasionally possible. We also detect a few large cells containing albumin and alpha-fetoprotein in the periductal area. Pancreatic hepatocytes have also been observed in the rat after recovery from copper deficiency diet. Thus, the regeneration of islet cells in transgenic mice provides a model system for the study of factors modulating the growth pattern as well as the differentiation pathway.


Trophic stimulation of the ductular-islet cell axis: a new approach to the treatment of diabetes.

We have established a model in which cellophane wrapping induces reiteration of the normal ontogeny of beta-cell differentiation from ductal tissue. The secretion of insulin is physiologic and coordinated to the needs of the animal. Streptozotocin-induced diabetes in hamsters can be "cured" at least 1/2 the time. There appears to be activation of growth factor(s) within the pancreas acting in an autocrine, paracrine or juxtacrine manner to induce ductal cell proliferation and differentiation into functioning beta-cells. Given the results of our studies to date, it does not seem premature to envisage new approaches to the treatment of diabetes mellitus. Identification of the factor(s) which regulate islet cell proliferation and differentiation in our model may permit islets to be grown in culture. This concept could be extended to induce endocrine cell differentiation in-vitro as well. Furthermore, islet cell growth factors could be used to provide "trophic support" to islet transplants as a means of maintaining graft viability. There may also be greater scope for gene therapy when the growth factor(s) has been isolated, purified, sequenced and cloned.


[Peri-orbital surgical approaches].

After having made a definitive diagnosis in patients with orbito-frontal pathology, the choice of incision is an important factor to achieve good intra-operative exposure of the region, as well as to obtain a good functional and aesthetic result. In the majority of cases we prefer to utilize the incisions commonly used for blepharoplasty, especially the transconjunctival approach popularized by Tessier. Other more classic accesses such as the superolateral, infra-orbital and intra-oral incisions, are reserved for treatment of cases of orbitomalar (communition) fractures. We feel there are limited indications for use of incisions through the eyebrows with medial extensions for exposure of isolated lesions of the medial orbital wall, orbital roof, and the anterior wall of the frontal sinus. However they may become very useful as the primary incisions in the treatment of open fractures of the orbital region. The bicoronal incision, a classical approach in neurosurgery, is also being used by us in cases of tumors and complicated middle face fractures which appear to extend to the orbito-frontobasal region in 40% of our patients. In addition it provides excellent access for post-traumatic reconstruction of orbito-frontal bone defects and impacted fractures. A combination of different incisions: bicoronal, peri-orbital and intra-oral, may be indicated for the correction of syndromal anomalies such as Treacher-Collins, for treatment of complicated facial fractures, or for pure aesthetic surgery procedures, such as the "mask-lift" introduced by Tessier.


Gingival localization of fibrosarcoma of soft oral tissues: case report.

A gingival localization of fibrosarcoma of soft oral tissues was described in a 58-year-old female. Primary fibrosarcoma of the head and neck region is rare. The histological appearance of the tumour is related to its grade of differentiation. The amount of collagen is variable. The accepted treatment is radical surgery; but metastases occur frequently in the lungs.


[Pedicled facial bone flap for closure of the approach in Caldwell-Luc type sinus operations. Its role in the prevention of postoperative complications].

The primary or secondary reconstruction of the facial access after Caldwell-Luc and the more selective resection of sinusal mucous membranes can be important in the therapy and prevention of postoperative complications such as neuralgic facial pain, formation of cysts and chronic sinusitis. The different osteoplastic sinus operations are described and the use of a pedicled bonelid is illustrated. The most common accepted ethiology of post-operative pain is based on the formation of scar-tissue. Postoperative pain is first being treated conservatively, while in case of persisting pain an exploration with dissection of the infra-orbital nerve and reconstruction of the facial defect can be indicated. In a retrospective study of 36 patients the results of our surgical therapy are illustrated.


[Complications of orbito-frontobasal fractures].

Complications of fronto-basal trauma can, as a function of their severity, be divided into three classes: life-threatening situations, functional complications and cosmetic defects or facial deformities. They find their origin in the type of trauma, the extent of the lesions of bone and soft tissues, as well as in their timely management and quality of treatment. The etiology of the most common complications and their significance are covered with accent on inadequate primary treatment, insufficient repair of dural lesions, inadequate drainage, unstable osteosynthesis, insufficient treatment of scalp- and frontal defects, and finally the lack of antibiotic prophylaxis. The major complications of frontobasal trauma such as chronic cerebral spinal fluid fistulae and pneumocephalus are reviewed. Attention is also given to the importance of adequate drainage in cases of chronic ethmoidofrontal sinusitis, and on the treatment of osteomyelitis and sinus cysts. The therapeutic possibilities in patients with tissue deficits, i.e. reconstruction of frontal skull defects using autologous hip and rib material, as well as split calvarial bone grafts is discussed.


Mechanisms of myocardial ischemia.

Traditionally, myocardial ischemia has been viewed as an imbalance in the supply and demand of myocardial oxygen. Stable angina is usually considered to involve a fixed lesion, whereas unstable angina involves a fixed lesion as well as such components as platelet aggregation, thrombotic processes, and vasospasm. Variant angina involves primarily vasospasm. A newer concept holds that most angina results from mixed mechanisms in which both fixed lesions and vasomotor alterations play a role. These mechanisms are responsible for mixed ischemic events, characterized by episodes at varying levels of exertion, with or without anginal pain. This concept would seem to be supported by the occurrence of silent ischemia in the setting of stable, unstable, or variant angina, despite differing pathophysiologic conditions. Ischemic events have important prognostic significance; unfortunately, many are unrecognized by patients. The question whether the treatment of ischemic events will improve prognosis remains a matter of debate.


New insights in measurement of myocardial ischemia.

Myocardial ischemia may be defined as myocellular dysfunction resulting from hypoxia usually due to limited coronary blood flow. The methods commonly used to make a diagnosis of myocardial ischemia employ either clinical findings (e.g., angina, myocardial infarction) or signals from laboratory tests. Since ischemia is often clinically silent and since clinical events related to ischemia may be catastrophic (i.e., myocardial infarction and sudden death), physicians are dependent on tests using various targeted signals. These signals, however, do not actually provide quantitative measurements of the degree of ischemia or related myocardial dysfunction. Nevertheless, the functional abnormalities reflected by these signals can identify patients at high or low risk for adverse outcomes related to ischemia. So, in this sense, these signals can be used to support the diagnosis of ischemia as well as evaluate its importance in a given patient. The most commonly used signal is an ST-segment shift evident on the electrocardiogram (ECG). When this is horizontal or downsloping and > or = 10 mm, this is often, but not always, due to myocardial ischemia. Although assessment of the exercise-stress ECG offers several advantages over assessment of the resting ECG, the standard Bruce protocol is associated with notable shortcomings that become apparent when an attempt is made to assess the effects of a treatment on the ST-segment signal. These might be surmounted by use of a continuous ramp-type protocol. Ambulatory ECG monitoring is growing in importance in the wake of increasing awareness of the different daily life circumstances that are associated with ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)


Treatment of chronic stable angina pectoris.

Patients with angina pectoris may be stratified into low- or high-risk categories on the basis of clinical findings and a careful workup, possibly including nuclear imaging of stress-induced abnormal perfusion or contractile patterns and coronary angiography. High-risk patients may require revascularization by angioplasty or bypass surgery, whereas low-risk patients can be managed medically. It is important to consider the impact of various anti-ischemic drugs on the myocardial demand-supply equation. A recent study indicated that the combination of a beta blocker plus isosorbide mononitrate is more effective in increasing exercise duration than is either the combination of a beta blocker and a calcium antagonist or triple therapy. In patients with single-vessel disease, angioplasty has been shown to be more effective than medical therapy in relieving symptoms, but the incidence of restenosis and the associated costs are high. Surgery favorably affects mortality in patients with left main coronary artery disease or 3-vessel disease with left ventricular impairment. New evidence suggests that endothelial dysfunction may play a more important role in chronic stable angina pectoris than has been appreciated and that such dysfunction may be treated with nitrates.


Pathophysiology of atherosclerosis.

New experimental evidence has shed light on a number of fundamental processes that contribute to atherosclerotic plaque formation. Recent data suggest that oxidized low-density lipoprotein (LDL) may be more avidly bound and taken up by macrophages, and thus more atherogenic, than unmodified LDL. A subclass of LDL, lipoprotein(a), is also of interest with respect to atherogenic potential, particularly since it has a plasminogen-like moiety as part of its structure. It may promote platelet aggregation and thrombus formation and thereby contribute to atherosclerotic plaque growth. Hypercholesterolemia, hypertension, and possibly other factors may induce changes in endothelial structure and function, which appear to be relatively early events associated with arterial injury. Smooth muscle cell proliferation and accumulation are hallmarks of arterial lesions induced by both hypertension and hypercholesterolemia, and several growth factors have been potentially implicated in these responses. Hypertension by itself causes arterial damage, but it does not appear to induce atherosclerosis when plasma lipid concentrations are low. In combination with hypercholesterolemia, however, it is a potent promoter of atherogenesis, and the mechanisms for this more-than-addictive effect are now the focus of considerable investigative attention.


Treatment of unstable angina pectoris.

Unstable angina pectoris may be manifested as new-onset angina, a change in the anginal pattern, pain at rest with associated electrocardiographic (ECG) changes, or postinfarction angina. Of these, pain at rest with ischemic ECG changes is known to be associated with the poorest prognosis. The pathogenesis of unstable angina pectoris involves a combination of a fixed atherosclerotic obstruction and a dynamic component related to coronary vasoconstriction, thrombus formation, or both. Long-acting nitrates, inhibitors of platelet aggregation, beta blockers, and calcium antagonists are among the agents that have been shown to be effective in the medical management of unstable angina. A study now in progress is evaluating the routine use of thrombolytic therapy for this indication. Although alleviation of symptoms and prevention of death and myocardial infarction are important therapeutic goals, the overall efficacy of a particular medical therapy can best be assessed by objective evaluation of its ability to control ischemia, using such techniques as exercise scintigraphy and ambulatory ECG monitoring. Cardiac catheterization and revascularization are indicated for patients with unstable angina who continue to experience symptoms or who show evidence of silent ischemia despite medical therapy. A study is under way to determine the advisability of routine revascularization of such patients. Revascularization will provide symptomatic relief in most patients with unstable angina and may prolong survival and improve left ventricular function in certain subsets.


Pharmacologic mechanisms of nitrates in myocardial ischemia.

Nitrates exert both hemodynamic and nonhemodynamic effects that help explain the mechanisms by which these drugs benefit patients with myocardial ischemia. The hemodynamic effects of nitrates include relaxation of conduit arteries, increased arterial compliance, increased venous capacitance, dilation of collateral vessels in the myocardium, and, possibly, increased myocardial compliance. A growing body of evidence suggests that the nonhemodynamic effects of these agents include inhibition of vascular smooth muscle growth and of myocyte hypertrophy and ventricular remodeling. Since endothelial function appears to be abnormal in patients with myocardial ischemia and nitrates replicate many of the effects of endothelium-derived relaxing factor, these drugs may be viewed as a pharmacologic replacement for deficient endogenous activity.


Tolerance, rebound, and time-zero effect of nitrate therapy.

Both nitroglycerin and long-acting nitrates have proved effective in treating acute anginal pain. In recent years, however, development of tolerance with the continuous use of these agents has been documented. A pilot study demonstrated attenuation of the therapeutic effect of high-dose, continuous transdermal nitroglycerin therapy, despite adequate plasma nitroglycerin levels. In a subsequent, larger Transdermal Nitroglycerin Cooperative Study, evidence of tolerance was detected within 24 hours of initiation of continuous nitroglycerin patch therapy at several different dose levels. Sustained pharmacologic activity has been achieved with the intermittent use of transdermal nitroglycerin, usually for 12 hours followed by a 12-hour drug-free period. When the patch is discontinued, however, some patients experience exacerbation, or rebound, of anginal symptoms and a worsening of exercise tolerance at the end of the drug-free period. Additional clinical research is therefore needed to determine the optimal intermittent dosing strategy.


Possible mechanisms of nitrate tolerance.

Prolonged exposure to organic nitrates has been shown to lead to the rapid development of tolerance to the peripheral and coronary vasodilatory effects of these drugs. As a result of this phenomenon, the hemodynamic and anti-ischemic effects of nitrates may be rapidly attenuated in patients with ischemic heart disease, congestive heart failure, or both. This nitrate tolerance appears to be both dose- and time-dependent. Likely mechanisms proposed for its development are multifactorial and include depletion of sulfhydryl groups, a nitrate-mediated increase in blood volume, and neurohormonal stimulation with activation of vasoconstrictive mechanisms.


Rationale for intermittent nitrate therapy.

Tolerance to the pharmacologic and therapeutic effects of nitrate therapy is now well established. This phenomenon may be defined as either a decreased response to a given amount of nitrate or the need for an increased amount of nitrate to maintain a constant effect. Tolerance has been demonstrated with all forms of nitrate therapy that maintain continuous blood levels of the drug, including frequent oral dosing, constant intravenous infusion, and continuous transdermal delivery. It can develop rapidly after only a few doses of a nitrate preparation and tends to be partial rather than absolute. Strategies for the prevention of nitrate tolerance include the avoidance of maximum nitrate doses and the use of intermittent nitrate dosing regimens. Providing a relatively brief nitrate-free interval restores vascular responsiveness to nitrates, most likely due to a recovery of the metabolic mechanisms responsible for the therapeutic effect of these drugs. The duration of this period of nitrate abstinence varies, depending on the nitrate preparation used but is generally in the range of 8-12 hours. Such intermittent therapy not only reduces the risk of nitrate tolerance, but also provides a convenient approach to outpatient management.


Pharmacokinetics of isosorbide mononitrate.

Pharmacokinetic studies show that isosorbide mononitrate is rapidly absorbed after oral administration, reaches peak concentrations within an hour, undergoes no significant first-pass metabolism, and is virtually 100% bioavailable. The half-life is approximately 5 hours, the volume of distribution is 0.62 liter/kg, and the systemic clearance is 115 mL/min. Only 1-2% of an orally administered dose is excreted unchanged in the urine, with the remainder being eliminated as inactive metabolites. Isosorbide mononitrate follows dose-linear kinetics after single and multiple doses. Its pharmacokinetic profile is consistent and highly reproducible and is unchanged in the elderly and in patients with coronary artery disease, renal failure, or liver cirrhosis. An asymmetrical dosage regimen of isosorbide mononitrate has been shown to provide antianginal efficacy for at least 12 hours. Because asymmetrical dosing creates irregular, sawtooth-like changes in plasma concentrations and a fall below a critical threshold level during the night, tolerance does not develop.


Efficacy of isosorbide mononitrate in angina pectoris.

The rapid development of tolerance has limited the applicability of oral and transdermal nitrates in the long-term management of patients with chronic stable angina pectoris. Recent well-controlled trials have demonstrated that asymmetrical, or eccentric, dosing of oral isosorbide mononitrate, in which 20-mg doses are taken at 8 A.M. and 3 P.M., provides at least 12 hours of antianginal coverage. There is no evidence for the development of tolerance with this schedule, which allows for a 17-hour nitrate withdrawal period. Likewise, the asymmetrical 20-mg twice daily regimen has not been associated with the zero-hour effect that has been reported with higher oral doses of isosorbide mononitrate and with intermittent nitroglycerin patch therapy. This approach also avoids the development of a clinical rebound phenomenon, as measured by increased episodes of angina and nitroglycerin consumption, compared with the pretreatment period, during the nitrate-free interval at night and the early hours of the morning.


New insights into the management of myocardial ischemia.

Episodes of ST depression are closely related to transient decreases in regional myocardial perfusion during physical or mental stress. At the onset of these events, there is transient constriction of atherosclerotic stenoses, with an increase in myocardial demand as reflected by increases in heart rate and blood pressure. Recent research has shown that normal epicardial coronary arteries respond to these provocations and to increasing blood flow with progressive vasodilation. In contrast, atherosclerotic vessels lose this ability to dilate and may show paradoxical constriction. This abnormal constriction parallels the response of the arteries to acetylcholine, which can be used to assess the ability of the coronary endothelium to regulate vasodilation. The loss of endothelium-dependent vasodilation appears to be an important functional manifestation of coronary atherosclerosis and a potential triggering mechanism for transient ischemia. Dysfunctional endothelium may also result in a procoagulant surface, with cell adherence and local thrombus formation. Restoration of normal endothelial function is likely to emerge as an important therapeutic objective in the management of myocardial ischemia and coronary atherosclerosis.


A phase I study of high-dose cisplatin, prolonged infusion 5-fluorouracil, and concomitant conventional fraction radiation therapy in patients with inoperable squamous cell carcinoma of the head and neck.

Cisplatin (CDDP) and 5-fluorouracil (5-FU) have been used alone, in combination, and in various doses and sequences with radiation therapy in attempts to improve local control and survival of patients with advanced head and neck cancer. This study was undertaken to determine the toxicity and maximum tolerated dose of high-dose CDDP plus prolonged infusion 5-FU with concomitant conventional radiation therapy. Twenty-two patients with inoperable Stage III and IV squamous cell cancer were treated with CDDP (30 or 35 mg/m2 for 5 days every 4 weeks for three courses) and 5-FU (200 or 300 mg/m2 per day continuous i.v. infusion for 12 weeks) with concomitant conventional radiation therapy. This aggressive treatment regimen is accompanied by severe mucositis, myelosuppression, and chronic neuropathy. CDDP, 35 mg/m2/day x 5, and 200 mg/m2/day of 5-FU infused over 12 weeks were identified as potential doses for future Phase II studies.


Phase I study of 5-fluorouracil with folinic acid combined with recombinant human granulocyte-macrophage colony-stimulating factor.

A Phase I study was conducted to determine whether the addition of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) to a combined 5-fluorouracil (5-FU) and folinic acid (FA) regimen would allow an escalated starting dose of 5-FU. FA (500 mg/m2) was administered as a 2-hour infusion on days 1 through 5, with 5-FU administered as a bolus injection 1 hour after the initiation of FA. Fifteen patients were enrolled in the trial; six were entered at a dose level of 375 mg/m2 of 5-FU, six at 450 mg/m2, and three at 540 mg/m2. rhGM-CSF was administered subcutaneously on days 6 through 15. A course of therapy was repeated every 28 days. Serious toxicity was observed at 450 mg/m2, with two patients developing grade 3 mucositis and one, grade 4 mucositis. Dose-limiting toxicity occurred at 540 mg/m2, at which point three patients developed grade 4 mucositis. One patient with metastatic colon cancer who received 5-FU at 540 mg/m2 achieved a partial response. Because of this persistent mucositis, the addition of rhGM-CSF used in this schedule would not allow an increased starting dose of 5-FU.


Radiation therapy in the treatment of pituitary adenomas.

Seventy-eight patients with pituitary adenomas were seen in the Department of Radiation Oncology at Hahnemann University between 1961 and 1986. Most were treated with megavoltage photons with or without prior surgery. In this group, 68 patients were followed: 39 were treated with radiation therapy (RT) alone, and 29 were treated with a combination of surgery and RT (S/RT). Patients were followed for 2 to 20 years. Of 68 patients, (97%) experienced complete response to treatment; 86% of the RT patients remained free of disease at 5 and 10 years. In the S/RT group, 100% and 94% remained free of disease at 5 and 10 years, respectively. Total disease-free survivals at 5 and 10 years were, respectively, 91% and 89%. The majority of the failures occurring in the RT group were with growth hormone-secreting tumors and Cushing's disease. Of the 7 patients that failed or recurred (time to recurrence: 1-16 years posttreatment), 6 have been followed: 4 were treated with surgery, 1 with RT, and 1 with S/RT. All 6 have remained free of disease since salvage, with 2- to 14-year follow-up periods. Serious morbidity and mortality have been reported previously with bitemporal field radiation using kilovoltage and low megavoltage RT. However, there was no temporal lobe necrosis or death in any of the patients in this study.


A phase II clinical trial evaluating the use of two sequential, four-drug combination chemotherapy regimens in ambulatory bronchogenic adenocarcinoma patients.

Forty-three ambulatory patients with locally advanced or metastatic bronchogenic adenocarcinoma were sequentially treated with two potentially mutually non-cross-resistant chemotherapy regimens. A new regimen, MVPF (mitomycin-c, vinblastine, procarbazine, and 5-fluorouracil), was given until progressive disease occurred. Then, a second regimen--MOCC (methotrexate, vincristine [Oncovin], cyclophosphamide, and CCNU)--was initiated. At further progression, regional disease patients received radiotherapy, whereas extensive disease patients received Phase II agents. Of the 43 patients entered on the study, 40 were evaluable. Three patients withdrew early due to poor tolerance of the regimen. The response rate for MVPF was 33% (12 of 40 PR, 1 of 40 CR) compared to a 4% (1 of 23 PR) response for MOCC (difference: p < or = .03), for a total response rate of 35%. Although there was an initial improvement in survival for responders (31.7 weeks) versus nonresponders (15.7 weeks) at the 75th percentile (p < or = .05), there was no significant difference in median survival. The hematologic toxicity was equivalent for both groups, whereas nonhematologic toxicity revealed a high incidence of nausea and vomiting in the MVPF group. It is concluded that this approach lent itself well to ambulatory care, and MVPF could be considered an alternative to cyclophosphamide-based regimens. However, the absence of a meaningful CR rate and lack of influence of response on median survival were factors limiting its effectiveness.


Lack of significant activity of 2'-deoxycoformycin alone or in combination with adenine arabinoside in relapsed childhood acute lymphoblastic leukemia. A randomized phase II trial from the Childrens Cancer Study Group.

Forty-nine children with recurrent acute lymphoblastic leukemia (ALL) were entered into a randomized Phase II trial evaluating 2'-deoxycoformycin (dCF) alone or in combination with adenine arabinoside (ara-A). 2'-Deoxycoformycin is an inhibitor of adenosine deaminase (ADA), an enzyme found in relatively high amounts in malignant lymphoid cells. Ara-A inhibits DNA polymerase and DNA synthesis. Because its efficacy in vivo as an anticancer agent is limited by its rapid inactivation by ADA, ara-A was combined with dCF to produce cytoreductive levels of ara-A. Twenty-four patients were assigned to receive dCF alone and 25 to receive the combination. No patient responded to dCF alone, and one patient developed a complete remission after treatment with the combination. The toxicity of dCF alone was minimal, except for one patient who became obtunded on day 5 following the first cycle of therapy. In contrast, five patients developed severe toxicity with the combination, including renal failure (three patients), hepatic failure (three patients), and neurologic toxicity (two patients). These results indicate that, at the doses and schedule used in this study, the combination of dCF and ara-A has significant toxicity and minimal activity against recurrent ALL in children.


5-fluorouracil and low-dose leucovorin in the treatment of recurrent epithelial ovarian carcinoma. A phase II trial of the Gynecologic Oncology Group.

Twenty-one patients with recurrent epithelial ovarian carcinoma not amenable to cure with further surgery or radiotherapy were entered into a Phase II trial utilizing i.v. leucovorin at 20 mg/m2 followed by i.v. 5-fluorouracil at 425 mg/m2 administered daily for 5 days every 4 weeks for the first two courses and then every 5 weeks. Twenty-one patients were entered. Of these, 20 were eligible for toxicity assessment and 19 for response. Five had received prior radiotherapy, and all had received prior cisplatin-based chemotherapy. There was one patient response (5.3%; 95% confidence intervals for response of 0% to 26%). Toxicity was moderate with 5 of 20 (25%) grade 3 or 4 leukopenia, 12 of 20 (60%) grade 3 or 4 granulocytopenia, 1 of 20 (5%) grade 3 thrombocytopenia, 5 of 20 (25%) grade 3 GI toxicity, and 2 of 20 (10%) grade 3 neurotoxicity. There was one toxic death in a patient who developed granulocytopenia and pneumonia after her third course of treatment. This dose schedule of 5-fluorouracil and leucovorin has minimal activity in patients with recurrent epithelial ovarian carcinoma who have received prior cisplatin chemotherapy.


5-fluorouracil and low-dose leucovorin in the treatment of recurrent squamous cell carcinoma of the cervix. A phase II trial of the Gynecologic Oncology Group.

Twenty-eight patients with recurrent squamous carcinoma of the cervix not amenable to cure by further surgery or radiation therapy were entered into a Phase II trial utilizing i.v. leucovorin 20 mg/m2 followed by 5-fluorouracil 425 mg/m2 administered daily for 5 days every 4 weeks for the first two courses and then every 5 weeks. One patient never received therapy, and three are inevaluable for response; therefore, 27 patients were evaluable for toxicity and 24 for response. Twenty-three patients had received prior radiotherapy, and 16 had received prior chemotherapy. There was one partial response 4.2% (95% confidence intervals for a response of 0 to 21%). Although toxicity was acceptable with 11 of 27 (41%) grade 3 or 4 leukopenia, 1 of 27 (4%) grade 3 thrombocytopenia, and 3 of 27 (11%) grade 3 or 4 gastrointestinal toxicity, this dose schedule of 5-fluorouracil and leucovorin has minimal activity in recurrent squamous carcinoma of the cervix.


Nonbacterial thrombotic endocarditis clinically mimicking veno-occlusive disease of the liver complicating autologous bone marrow transplantation.

Nonbacterial thrombotic endocarditis is an uncommon, but well-described, complication of bone marrow transplantation. We describe a case of nonbacterial thrombotic endocarditis following autologous bone marrow transplantation that was marked by weight gain, hepatomegaly, ascites, and extreme hyperbilirubinemia leading to a clinical diagnosis of hepatic veno-occlusive disease. Autopsy revealed nonbacterial thrombotic endocarditis of the tricuspid and pulmonic valves, and passive congestion of the liver, but there was no evidence of veno-occlusive disease. We discuss the pathophysiology and clinical features of nonbacterial thrombotic endocarditis and review its occurrence in association with bone marrow transplantation. Nonbacterial thrombotic endocarditis is often difficult to detect clinically and should be a diagnostic consideration in patients who develop systemic emboli or congestive heart failure after bone marrow transplantation.


A phase II study of cisplatinum and continuous infusion 5-fluorouracil for metastatic melanoma.

Advanced or metastatic melanoma responds poorly to chemotherapy, which has no impact on survival. Responses have been recorded using cisplatinum as a single agent. This study tested the established combination of cisplatinum 100 mg/m2 and 5-fluorouracil 1 g/m2/day continuously intravenously for 5 days repeated every 3 weeks in patients with disseminated melanoma. Twenty-nine patients, 13 having received no prior systemic chemotherapy, received 49 cycles of therapy (median 1, range 1-4). Only one previously untreated patient achieved a partial response with a failure-free survival of 6.5 months and an overall survival of 7.7 months from the commencement of therapy. The major toxicities were nausea and vomiting, (grade 3 in eight patients), stomatitis (grade 4 in two patients, grade 3 in two patients), and myelosuppression. The study showed that cisplatin and 5-fluorouracil have a low order of activity in patients with advanced or disseminated melanoma.


Treatment of Langerhans cell histiocytosis in children with etoposide.

Ten children with Langerhans cell histiocytosis (LCH) were treated with etoposide. For five patients, this was the initial diagnosis. The other five had failed to respond to previous therapies. Etoposide (100 mg/m2) was given intravenously twice a week for 4 weeks, followed by maintenance therapy every 2 to 4 weeks for 2 years. All 10 patients responded to etoposide, and 6 of them (60%) have been in complete remission for 3 to 36 months without any side effects. One patient relapsed with diabetes insipidus, one with a soft tissue mass, and two others developed multiple bone lesions. Chemotherapy with etoposide appears to be effective and safe for the treatment of children with systemic LCH.


Systemic infusion versus bolus chemotherapy with 5-fluorouracil in measurable metastatic colorectal cancer.

From January 31, 1986 to January 31, 1989, 184 eligible patients were enrolled in a randomized study of either infusional or bolus 5-fluorouracil (5-FU) for the treatment of metastatic measurable colorectal cancer. Infusion was administered at an escalated dose schedule starting at 350 mg/m2 per day for 2 weeks with a 2-week rest period on a monthly basis, while bolus 5-FU was started at 400-450 mg/m2 for 5 days every 28 days. In these chemotherapy-naive patients with good performance status, the infusion arm produced a response in 11 of 88 patients versus 6 of 82 in the bolus arm (p = 0.384). Progression free survival was significantly longer (p = 0.0139) in the infusion group (3.8 versus 2.3 months), but no significant difference in survival was observed (p = 0.207). As expected, the toxicities of the regimens were different in character, but each had approximately a 20% incidence of significant toxicities. Neither of these methods of administering fluorouracil results in an exceptional response rate, nor does the infusion have an impact on survival as compared to the bolus route. If this type of complicated infusional approach is to continue, especially with increasing dosage (which could be accomplished on our schedule), randomized studies with survival as an endpoint must remain the gold standard.


Phase II evaluation of iproplatin in patients with advanced gastric and pancreatic cancer.

A total of 48 patients with measurable advanced gastric adenocarcinoma (n = 16) or adenocarcinoma of the exocrine pancreas (n = 32) were prospectively treated with iproplatin at a starting dose of 270 mg/m2 intravenously over 2 hours. The dose was repeated every 28 days, and dose escalations or reductions were made on the basis of toxicity in the preceding course. No patient with gastric carcinoma achieved either a complete or partial response. One partial response and two complete responses were seen with pancreatic adenocarcinoma for an overall response rate of 10%. One patient has remained free of disease for more than 2 years. The major toxicities were granulocytopenia, thrombocytopenia, nausea, vomiting, and diarrhea. All toxicities were reversible upon discontinuation of the drug. On the basis of this trial, we conclude that iproplatin has no substantive activity in advanced gastric or pancreatic carcinomas.


Successful therapy of peritoneal mesothelioma with intraperitoneal chemotherapy alone. A case report.

Malignant peritoneal mesothelioma is a disease that remains relatively refractory to conventional intravenous chemotherapy with currently available agents. Single-agent and combination chemotherapy offer a response rate of 20%. Direct intraperitoneal administration of some chemotherapeutic agents results in a significant pharmacologic advantage with much greater area under the concentration versus time curve (AUC). We report a case of a patient with peritoneal mesothelioma treated with combination intraperitoneal cisplatin and Ara-C who achieved a pathologic complete remission. This patient is still alive and has been in complete remission for 53 months. This combination of intraperitoneal chemotherapy deserves further evaluation in malignant mesothelioma.


DAE (daunorubicin, Ara-C, and etoposide) and intermediate dose Ara-C for remission induction and consolidation treatment of adult patients with acute myeloid leukemia.

Fifty-one patients (age 18-73 years) with acute myeloid leukemia were treated with daunorubicin, cytarabine, and etoposide in an age-adjusted protocol, with patients older than 50 receiving fewer days of therapy. Complete remission (CR) occurred in 66% of the patients (34 of 51 patients). Patients 50 years of age and younger achieved a 74% CR rate (23 of 31 patients) compared to a 55% CR rate (11 of 20 patients) in older patients. Of the 34 complete responders, 11 (32%) refused consolidation therapy and received traditional Chinese herbal medicine. All of these 11 patients relapsed after a short remission duration (median, 3.8 months) and died. The median remission duration and median overall survival of 23 complete responders receiving at least two courses of consolidation therapy were 10.1 and 19.8 months, respectively. The actuarial 3-year disease-free survival for these 23 complete responders was 21 +/- 9%. Myelosuppression was the major toxicity, and nonhematological side effects were acceptable. The regimen appeared to have acceptable toxicity, and its efficacy was comparable with that of standard regimens with long-term maintenance therapy.


Substance use and work disabilities among a general population.

Using data derived from a representative survey of 869 Ontario adults, we examined the association between work disabilities and substance use, i.e., drinking, alcohol problems, sleeping pills, and tranquilizers. Overall, we found a significant association between substance use and disability. For alcohol problems, we found that those with moderate limitations reported the greatest number of problems, holding constant age, gender, income, and frequency of drinking. For the use of sleeping pills and especially tranquilizers, we found a strong positive relationship to limitation status. A number of significant interactions involving tranquilizer use showed that two groups, females with total limitations and those aged over 40 years with sensory disabilities, reported exceptionally high rates of tranquilizer use.


High-risk sexual behaviors of intravenous drug users in- and out-of-treatment: implications for the spread of HIV infection.

This paper examines the sexual behaviors of 255 intravenous drug users (IVDUs) to assess the potential for the sexual transmission of HIV and to examine differences in sexual behaviors between in- and out-of-treatment IVDUs. In-treatment subjects (N = 152) were a random sample of clients at a large, publicly funded methadone maintenance program. Out-of-treatment subjects (N = 103) were recruited through a chain referral technique, using the in-treatment subjects. Forty-five percent of the study subjects reported multiple partners and 32% reported exchanging sex for money or drugs in the preceding 6 months. Fifty-three percent reported no use of condoms. After controlling for demographic differences between the in- and out-of-treatment groups, out-of-treatment IVDUs reported significantly more partners than in-treatment IVDUs (4.6 vs 2.3, significant t < 0.01), and more often had exchanged sex for money or drugs (44 vs 26%, relative odds 1.8, p < .05). In- and out-of-treatment subjects did not differ with respect to condom use. We conclude that IVDUs both in- and out-of-treatment continue to be at risk of contracting and spreading HIV infection through sexual behaviors, and that being in drug treatment is associated with a lower incidence of high risk sexual behaviors.


Abuse of monoamine oxidase inhibitors.

Monoamine oxidase inhibitors, like other antidepressants, generally are considered free of risk for abuse. There is, however, some evidence that MAOIs possess dependence and abuse potential for some patients. We will review the available literature and describe three current cases. Recommendations for treatment are discussed briefly.


Assessing treatment effects through changes in perceptions and cognitive organization.

This investigation tested the Associative Group Analysis (AGA) for its analytic sensitivity in assessing perceptions and attitudes and in mapping changes in cognitive organization indicative of substance abuse. Based on inferences drawn from the distributions of thousands of spontaneous, free associations elicited by strategically selected stimulus themes, AGA offers an unstructured approach to assess images and meanings, and to map systems of mental representation evasive to the more direct methods of using questions or scales. This article compares pretreatment and posttreatment samples, tracing the psychosocial effects of treatment. The investigations focus on variables related to substance abuse such as self-image, social nexus, and perceptions of illicit substances. The results indicate a sensitive approach, useful in treatment evaluation.


The relationship of pretreatment family functioning to drinking behavior during follow-up by alcoholic patients.

The relationship of alcoholics' perceptions of the pretreatment functioning of their families to drinking outcomes during an 18-month follow-up was examined. Family functioning was hypothesized to be predictive of drinking behavior, particularly in subjects with low assertion of autonomy scores. These individuals report greater dependency and attachment, and therefore might be more affected by the state of important relationships. The results indicated that with low autonomy male alcoholics, greater family dysfunction predicted significantly fewer days abstinent during Months 1-6 and 13-18 and more severe drinking episodes during the first year of the follow-up. In the high autonomy males, family dysfunction was unrelated to subsequent drinking behavior. In women, on the other hand, greater family dysfunction predicted more days abstinent in those high in autonomy and was unrelated to the drinking behavior of those low in autonomy. Implications for patient-treatment matching, differences between male and female alcoholics, and the need for additional studies of family functioning and drinking behavior in women are discussed.


Alcohol norms and expectations as predictors of alcohol use and problems in a college student sample.

Two-hundred thirty-one alcohol-using college students completed a questionnaire on their levels of alcohol use, moderate to severe problems with alcohol use, expectations of the effects of alcohol on their own and others' moods and behaviors, the desirability of these effects, norms of significant others for levels of alcohol use and the subject's desire to comply with these norms, reasons for drinking and not drinking alcohol, and a personality measure. Expectations of alcohol effects, norms of significant others, and reasons for drinking and not drinking alcohol were all significant independent predictors of alcohol use and problems with alcohol use. Expectation x desirability of effects formulations and norms x desire to comply with norms formulations did not improve the predictive power of the expectations and norms scales.


Cognitive motivations for drinking among alcoholics: factor structure and correlates.

The aims of this study were to: a) Identify factors reflecting reasons for drinking and expectancies regarding the effects of drinking among inpatient alcoholics; b) Examine the relationship between these cognitive "motivations" for drinking and both patterns of alcohol consumption and various personal and social consequences of consumption. The factors which emerged relate to negative mood reduction, positive mood enhancement, and social functioning. Although the factors identified in this investigation were not associated with quantity of alcohol consumed, small to moderate associations were found between scores on three of four factors and a variety of adverse physical and occupational consequences of alcohol abuse.


Hepatotoxicity of nonsteroidal anti-inflammatory drugs.

The steady increase in nonsteroidal anti-inflammatory drug (NSAID) use over the past decade has been associated with an increased awareness of the gastrointestinal complications of these agents. As a result, several reviews on this topic have been published. Associated with the increased recognition of the untoward gastrointestinal consequences of NSAID use has been an increasing awareness of the untoward hepatic consequences of NSAID use. Nonetheless, many physicians either remain unaware of the hepatotoxic potential of NSAIDs or are unsure which agents are either safer or associated with a greater risk for hepatotoxicity. The following is an overview of the hepatotoxicity of NSAIDs that identifies both the type and severity of such reactions, where sufficient data exist to allow such judgements to be made.


Return of esophageal peristalsis after nifedipine therapy in patients with idiopathic esophageal achalasia.

This study was carried out to demonstrate the possible return of esophageal peristalsis in patients affected by esophageal achalasia chronically treated with sublingual nifedipine and to investigate which parameters are correlated with the return of peristalsis. Thirty-two patients were treated with sublingual nifedipine 10-20 mg taken 30 min before meals. A clinical and manometric evaluation was performed before and after 6 months of therapy. Before treatment, in no patient was peristaltic activity recorded. After 6 months, peristalsis was observed in six patients. In this group, no pretreatment manometric parameter was different from that of the remaining achalasic patients; only the clinical history of dysphagia was significantly shorter (p < 0.001) and the esophageal diameter significantly less (p < 0.001). In conclusion, chronic treatment with sublingual nifedipine can induce a return of esophageal peristalsis in patients with a short clinical history of disease and slightly dilated esophagus.


The importance of fluoroscopic guidance for Maloney dilation.

One hundred and forty-five patients were evaluated for the importance of fluoroscopic monitoring during Maloney esophageal dilation. In 35 patients (24%), fluoroscopy altered the dilation technique. Dilation of peptic strictures (27 of 75, 36%) was much more likely to be affected by fluoroscopy than Schatzki's rings (eight of 70, 11%, p < 0.05). Patients whose stricture was altered by fluoroscopy also had larger size hiatal hernias (6.5 vs. 4.3 cm, p < 0.05). Patients with Schatzki's ring with a hiatal hernia size of less than or equal to 4.0 cm did not benefit from fluoroscopy. In 26 of 35 cases, successful redirection of the dilator and passage under fluoroscopy was accomplished. In nine patients, Maloney dilation was impossible, and use of Savary wire-guided dilators was needed. We had no morbidity and mortality. We advise the use of fluoroscopy for Maloney dilation for peptic strictures and for large hiatal hernias.


Abnormal upper esophageal sphincter function in achalasia.

We describe the results of pharyngeal and upper esophageal sphincter (UES) manometry, using new solid-state computerized technology in 19 patients with achalasia, compared with 14 healthy controls. The major manometric finding in achalasia is an increased residual pressure in the UES. Other differences seen in patients with achalasia include a reduction in the duration of UES relaxation with swallowing and a more rapid onset of pharyngeal contraction after UES relaxation. We review previous descriptions of suspected pharyngeal and UES abnormalities in achalasia and compare them to our own.


Meta-analysis of the efficacy of antibiotic therapy in eradicating Helicobacter pylori.

Despite numerous Helicobacter pylori treatment studies, the optimum regimen(s) for its eradication remain unclear. Our objective was to determine systematically which regimen(s) gave the best pooled eradication rates, by using meta-analysis methodology. A total of 27 studies were identified. Pooled eradication rates for single (18.6%), double (48.2%), and triple therapy (82.3%) were statistically highly different (p < 0.0005). Eradication rates with amoxicillin (23.0%) and bismuth compounds (19.6%) were equivalent. Combined treatment with bismuth+metronidazole was better than bismuth+amoxicillin (55.1% vs. 43.7%, p = 0.049). Triple therapy with bismuth+metronidazole+tetracycline gave a statistically higher eradication rate (94.1%) than bismuth+metronidazole+amoxicillin (73.1%, p < 0.0005). Despite increased side effects with multiple antibiotic regimens, patients tolerated these well, without significant drop-out. The combination of bismuth, metronidazole, and tetracycline gives the best eradication rate, but the optimal doses and duration of treatment have yet to be determined. Further studies are necessary to explore factors such as antibiotic resistance and drug compliance as important factors affecting antibiotic efficacy.


Helicobacter pylori infection in dental workers: a seroepidemiology study.

The finding of Helicobacter pylori in dental plaque suggested that dental workers may be at increased risk of acquiring H. pylori infection from occupational exposure. A cross-sectional survey of 239 dental workers from 37 Texas cities (including 89 dentists, 44 dental hygienists, 98 dental assistants, and eight dental students) was conducted. H. pylori infection was determined by the presence of IgG antibodies to H. pylori, using a specific and sensitive ELISA. Participants ranged in age from 19 to 72 yr (mean 34 yr) and the duration of dental practice ranged from 1 to 48 yr (mean 12 yr). Type of dental occupation, duration of practice, type of practice (public or private), instrument used for cleaning teeth (ultrasonic scaler or curette), and prevalence of upper gastrointestinal symptoms were determined by self-administered questionnaires and interviews. Eighty-two percent had no symptoms referable to the upper gastrointestinal tract. The overall prevalence of H. pylori infection was 24%: 17% in dentists, 18% in dental hygienists, 34% in dental assistants, and 25% in dental students. The prevalence increased significantly with age (p < 0.05). The prevalence of H. pylori infection was significantly higher in non-whites, 29 of 63 (46%), than whites, 29 of 176 (16%) (p < 0.001). Logistic regression analysis (dependent variable H. pylori) revealed no significant association between H. pylori infection and the type, duration, or volume of practice, or the type of cleaning instrument used. We conclude that dental workers are not at increased risk to H. pylori infection.


An unrecognized etiology for pyogenic hepatic abscesses in normal hosts: dental disease.

Cryptogenic pyogenic hepatic abscesses are a diagnosis of exclusion. We have identified two patients with severe dental disease at the time of the diagnosis of their liver abscess. In both cases, oral flora was cultured from the abscess. Unlike a previous report, both patients were immunocompetent. When compared with a group of patients with liver abscesses and diverticulitis, two differences were found. In contrast to the single abscesses seen in 10 of 10 patients with diverticulitis, the patients with dental disease had multiple abscesses (p < 0.02). In addition, Fusobacterium nucleatum was cultured from both dental disease associated abscesses but only one of the diverticulitis associated liver abscesses (p < 0.05). If a liver abscess is thought to be cryptogenic, a thorough dental exam is recommended.


Safety and efficacy of high kV biliary lithotripsy: preliminary experience.

Despite intense interest in laparoscopic cholecystectomy, biliary lithotripsy (BL), by avoiding the need for general anesthesia, could remain a useful alternative in approximately 10% of patients with symptomatic gallstones. The poor stone clearance rates reported by the Dornier National Biliary Lithotripsy Study has led to disenchantment with biliary lithotripsy. However, the results may reflect the relatively low kV (18.7 +/- 1.7) used. We have compared symptomatic gallbladder stone/cholecystolithiasis patients with one to five stones of aggregate diameter < 60 mm treated with one to three sessions on an MPLS 9000 (Dornier) lithotripter at moderate kV (22.7 +/- 1.7 kV; mean number of shocks 1473 +/- 356) with a similar group treated with high kV (26 kV, mean number of shocks 1357 +/- 507). Ultrasound stone diameter measurements were made pre- and post-BL; 12-wk results are reported. Treatment safety was assessed by recording adverse experiences and serum, urine, hematology, and chemistry. For patients with single stones, the high kV treatment took significantly (p < 0.05) less time (74 +/- 30 min) than moderate kV treatment (118 +/- 33 min). At 3 months, the moderate kV-treated single-stone group had a residual maximum fragment size of 3.2 +/- 3.3 mm versus 1.8 +/- 2.3 mm in the high kV-treated single-stone group. The 3-month stone-free rate for patients with single stones treated at high kV was 44% compared with 46% for the moderate kV-treated group (NS). At 1 wk, 11 patients had microscopic or macroscopic hematuria and six patients had mildly elevated liver function tests. At 6 wk, however, all urine and hematological measurements had returned to normal. Two patients suffered pancreatitis, one in each group. High kV BL appears to be safe and, for patients with single stones, gives better fragmentation and takes less time to administer than moderate kV. Whether a high kV treatment protocol can achieve improved long-term stone-free rates remains to be assessed.


Gastric and duodenal mucosal prostaglandin concentrations in gastric or duodenal ulcer disease: relationships with demographics, environmental, and histological factors, including Helicobacter pylori.

We measured gastric and duodenal mucosal prostaglandin concentrations in 69 patients with active or inactive duodenal or gastric ulcer disease and 26 non-ulcer controls. Each underwent endoscopy enabling us to obtain multiple biopsies from the gastric body and antrum and from the duodenal bulb and postbulbar duodenum for measurement of mucosal prostaglandin concentrations, as well as a single biopsy from each region for mucosal histology. Using a multivariate linear regression model, we found that neither gastric nor duodenal ulcer disease significantly affected gastric or duodenal mucosal prostaglandin concentrations. Mucosal prostaglandin concentrations were similar at the edge of the ulcer and in the adjacent non-ulcerated mucosa. Neither gender symptoms, smoking, use of H2-receptor antagonists, disease activity, nor Helicobacter pylori infection had an independent effect on mucosal prostaglandins in any region. Gastritis in the body of the stomach was associated with significantly higher prostaglandins, while older age was associated with significantly lower gastric and duodenal prostaglandins. Gastroduodenal mucosal prostaglandins are thus not altered in patients with active or inactive peptic ulcer disease, even when multiple demographic and histologic variables are taken into consideration.


Flexible sigmoidoscopy screening in an industrial setting.

Little is known about the yield of colorectal cancer screening programs in an industrial setting. We therefore established a flexible sigmoidoscopy screening program at a chemical manufacturing plant and offered testing to all employees over the age of 40. After a Fleet enema preparation had been administered, a digital rectal examination and sigmoidoscopy were performed on each volunteer worker in the medical office of the plant. The plant had an average census of about 650 workers; 202 were screened during a 2-yr period. The mean (+/- SEM) age of participants was 52 +/- 0.4. Sixty-four employees had polyps (31.7%); data on follow-up colonoscopy were available in 69%. Colonoscopy revealed adenomatous polyps in 23 workers (53.5%), hyperplastic polyps in 10 (23%), and no evidence of neoplasia in 10 (23%). Seven workers did not arrange for follow-up colonoscopy and 12 individuals could not be contacted. No cancers were detected. In the 40- to 50-yr age group, polyps were detected in 19.5% of employees (25% adenomatous). Incidental findings were common, and included prostatic nodules, hemorrhoids, diverticulosis, and proctitis, among others. We conclude that screening sigmoidoscopy can be conveniently and economically performed at the workplace, with a high yield and good worker acceptance. The high yield suggests a possible association between polyp formation and work in a chemical plant. The finding of adenomatous polyps in the younger patients suggests that the threshold for flexible sigmoidoscopy at age 50 needs to be reassessed.


Gastrointestinal pneumocystosis in HIV-infected patients on aerosolized pentamidine: report of five cases and literature review.

Extrapulmonary infection with Pneumocystis carinii in AIDS patients on aerosolized pentamidine is occurring more frequently. We report five patients diagnosed with gastrointestinal pneumocystosis while on aerosolized pentamidine prophylaxis and have identified infections involving the peritoneum, liver, and transverse colon, as well as stomach and duodenum. Physicians should have a high index of suspicion for extrapulmonary pneumocystosis, especially involving the gastrointestinal system, in HIV-infected patients, and early diagnosis must be pursued aggressively. The use of aerosolized pentamidine as prophylaxis for P. carinii pneumonia is not protective against gastrointestinal pneumocystosis because of inadequate systemic distribution of the drug. To our knowledge, this is the first report in a clinical journal documenting and photographing P. carinii organisms in ascitic fluid.


Clinical, endoscopic, immunologic, and therapeutic aspects of oropharyngeal and esophageal candidiasis in HIV-infected patients: a survey of 114 cases.

The medical records of 114 consecutive HIV-infected patients with oropharyngeal and esophageal candidiasis, in whom esophagoscopy was performed, were reviewed. Esophageal candidiasis and isolated oral candidiasis were found in 75% and 25% of patients, respectively. Esophageal candidiasis was the AIDS-defining illness in 65 patients and dysphagia was the commonest symptom, but asymptomatic Candida esophagitis was observed in 43% of them. Symptoms were present in six patients with oropharyngeal candidiasis; three of them had a normal esophagoscopy and the other three had acute nonfungal esophagitis. Invasive fungal esophagitis was confirmed by biopsy in 47/74 patients (64%). The patients with esophageal candidiasis had lower CD4+ cell counts (129/microliter) and CD4:CD8 ratios (0.23) than those with oropharyngeal candidiasis (CD4 179/microliter; CD4:CD8 0.35). Thirty-six patients with esophageal candidiasis were treated with fluconazole, 100 mg/daily, for 28 days, and another 34 patients received the same dose for 10 days. A similar efficacy was seen in both regimens, but a higher incidence of oropharyngeal fungal colonization and liver dysfunction was observed in the longer therapy (p < 0.001). We conclude that asymptomatic C. esophagitis is common in HIV-infected patients. Patients with oropharyngeal candidiasis may complain of esophageal symptoms; it could be due to superficial C. infection or another not-identified opportunistic infection. More severe immunologic impairment was required to develop esophageal candidiasis than oropharyngeal candidiasis. A short course of 10 days of fluconazole therapy could be the standard regimen for the treatment of C. esophagitis in AIDS.


Gastric acid secretion in HIV-1 infection.

It has been suggested that AIDS patients may have reduced gastric acid output. This is of concern because gastric acid may be required for absorption of oral antifungal agents that are important in AIDS management. The cause as well as the progression of reduced gastric acid output in AIDS patients is unclear. This study investigated gastric acid output in relation to the stage of non-AIDS HIV-1-infected patients. No statistical difference was found between nine control and 26 male HIV-infected subjects in basal acid output, maximal acid output, peak acid output, or fasting serum gastrin, regardless of stage. Likewise, no relationship between stage of HIV infection and gastric acid output was determined. We conclude that there is no impairment in basal and maximally stimulated gastric acid secretion in non-AIDS HIV-1-infected males. In addition, the clinical stage of non-AIDS HIV-1 infection has no effect on gastric acid secretion.


Decreased intrinsic factor secretion in AIDS: relation to parietal cell acid secretory capacity and vitamin B12 malabsorption.

AIDS-associated gastric secretory failure has been characterized by decreased secretion of acid, pepsin, and gastric juice volume. To determine whether decreased intrinsic factor secretion and vitamin B12 malabsorption occur in this entity, we performed prospective measurements of maximal acid output, intrinsic factor output, vitamin B12 absorption, serum vitamin B12, and holotranscobalamin II in 10 consecutive AIDS patients. Four of 10 patients had low maximal acid output, i.e., < or = 1.5 mEq/h (control = 12.8 +/- 9.0, range 2.5-25 mEq/h). Four patients had low intrinsic factor output, i.e., < or = 1.1 microgram/h (control = 8.2 +/- 6.9, range 3.1-19.4 micrograms/h). One patient with low intrinsic factor output had low serum vitamin B12 and a Schilling test consistent with pernicious anemia. A second patient with very low intrinsic factor output (0.16 micrograms/h) had low parts I and II Schilling tests; malabsorption most likely resulted from both low intrinsic factor secretion and ileal disease. One of three vitamin B12 malabsorbing patients, with normal serum vitamin B12, had low holotranscobalamin II, 25 pg/ml (control holotranscobalamin II = 76 +/- 44, range 44-152 pg/ml). Maximal acid output and intrinsic factor output did not correlate in AIDS (r = 0.36, p = 0.30) in contrast to the expected correlation in controls (r = 0.91, p = 0.03). We conclude that low intrinsic factor secretion is common in AIDS and contributes to vitamin B12 malabsorption. Decreased parietal cell secretion of intrinsic factor and acid may occur independently in human immunodeficiency virus-associated gastric secretory failure. Low holotranscobalamin II, an early manifestation of vitamin B12 malabsorption, results in decreased delivery to vitamin B12-dependent tissues prior to depletion of serum vitamin B12. Regular supplementation with vitamin B12 may therefore be warranted in patients with advanced HIV infection.


Treatment of intractable hiccup with baclofen: results of a double-blind randomized, controlled, cross-over study.

Four patients with intractable hiccup were treated in a double-blind, randomized, placebo, cross-over study with an analogue of gamma-aminobutyric acid, Baclofen. There was a consistent and statistically significant (p = 0.03) improvement in hiccup severity with Baclofen, both subjectively (p = 0.03) and by hiccup-free periods (p = 0.003). The actual frequency of hiccup was not significantly altered by the medication. We propose that the mechanical aspects of hiccup are reduced by Baclofen, leading to a perceptual blockage and a decrease in the reflex severity induced by the gamma-aminobutyric acid analogue. We conclude that this medication may be useful for the treatment of intractable hiccup.


Prognostic factors of hepatic encephalopathy after portacaval anastomosis: a multivariate analysis in 50 patients.

Portacaval anastomosis has proved to be effective in avoiding active and recurrent hemorrhage from gastroesophageal varices in liver cirrhosis. However, hepatic encephalopathy is the most common and serious complication of this procedure. The aim of this study was to investigate by multivariate analysis the predictive factors of development of hepatic encephalopathy in 50 Child's A and B cirrhotic patients whose variceal bleeding was treated with emergency (n = 17) or elective (n = 33) portacaval anastomosis. The etiology of the cirrhosis was alcoholic in 74% of cases. The mean follow-up was 22.7 +/- 16.6 months (range 1-60 months). The 2-yr probability of suffering from at least one episode of hepatic encephalopathy in the overall group was 43%. The multivariate analyses (Cox's regression method) of 37 variables based upon clinical history, physical examination, and laboratory data disclosed that only five of these variables had independent predictive value: need for diuretic treatment in the days prior to surgery, absence of hepatomegaly, and serum levels of total bilirubin, gamma-globulin, and hemoglobin. According to the contribution of each one of these factors to the final model, a prognostic index was obtained which allowed the division of patients in two different groups of risk for developing hepatic encephalopathy (20% and 74%, respectively, after 2 yr of surgery; p = 0.0002). This index may help to better choose those candidates for portacaval anastomosis.


Endoscopic sclerotherapy: treatment of choice in patients less than 3 years old with extrahepatic portal vein obstruction.

Thirty-two children under 3 yr of age with extrahepatic portal vein obstruction were treated with endoscopic sclerotherapy. The group consisted of 22 males and 10 females, with a mean age of 1.96 yr (range 7 months to 3 yr). The procedure was well tolerated by all after premedication with intravenous diazepam. Esophageal varices were eradicated in all children after 4.45 sessions (+/- 1.12). Follow-up clinical and endoscopic evaluations have been carried out over a period of 9 months to 4 yr (mean 3.5 yr) after the patients were put on a sclerotherapy program. There was a significant reduction in number of bleeding episodes (60 vs. 8), mean blood transfusion requirement (2.19 vs. 0.31), and bleeding risk factor (0.09 vs. 0.008). There were a few minor conditions, such as transient dysphagia and esophageal ulcerations, in 14 patients (43.75%), which later responded to medical treatment. Perisclerotherapy bleeding, seen in six patients (18.7%), responded to repeat sclerotherapy. Recurrence of varices was encountered in two patients (6.25%); these were eradicated after reinstitution of sclerotherapy. Endoscopic sclerotherapy is the treatment of choice in patients of extrahepatic portal vein obstruction who are below 3 yr of age.


Bile duct varices or "pseudo-cholangiocarcinoma sign" in portal hypertension due to cavernous transformation of the portal vein.

A total of 832 patients with portal hypertension resulting from different etiology was studied by ultrasonograph as a screening test. In 17 of the 832 patients, cavernous transformation of the portal vein was detected by means of ultrasonography. We have prospectively studied these 17 patients, and the diagnosis of cavernous transformation was confirmed by portography in all patients. To evaluate how much biliary tract has been affected from cavernous transformation of the portal vein, and to explain the cause of mildly increased alkaline phosphatase and serum bilirubin levels, endoscopic retrograde cholangiopancreatography (ERCP) was performed in 16 of the 17 patients. There were narrowing, irregularity, undulation and nodular extrinsic defects resulting from compression of thrombosis of the portal vein and the collateral vessels, mimicking cholangiocarcinoma spreading along the common bile duct on the extrahepatic biliary tract in all 16 patients who underwent ERCP. Similar ERCP findings were not found in six patients with portal hypertension due to liver cirrhosis. The ultrasonographic, portographic, and ERCP findings corresponded to surgical findings in six patients who had undergone splenectomy for either hypersplenism or bleeding from esophageal varices. The results indicate that cavernous transformation of the portal vein cause the above-mentioned radiographic findings that we propose to call "pseudo-cholangiocarcinoma sign."


Factors influencing acceptance of hepatitis B vaccination by hospital personnel in an area hyperendemic for hepatitis B.

A free-of-charge vaccination program against hepatitis B, in which plasma-derived vaccine was used, was offered to 1,299 hospital personnel of Chulalongkorn University Hospital, Bangkok. The initial acceptance rate for vaccination was 65.7%, with 10.0% nonacceptance and 24.3% undecided. The highest rates of acceptance were among medical students (75.5%), student nurses (68.8%), and newly graduated nurses (63.6%). The lowest rate of acceptance was among physicians (48.2%). Factors strongly associated with the acceptance of vaccination were nature of work, age of personnel (< or = 40 yr), number of years spent in profession (< or = 15 yr), knowledge of hepatitis B, confidence in vaccine efficacy and safety, no history of hepatitis B infection, and contact with blood or blood product. Different types of fear, as well as lack of knowledge, were the main reasons responsible for 46.2% of all refusals. More specific educational efforts about vaccine safety and efficacy may positively influence the acceptance of hepatitis vaccination program among health care personnel.


Can cytokines prolong survival in ampullary neuroendocrine carcinomas?

Herein we report the case of an ampullary tumor in a 53-yr-old Japanese woman who presented in March 1988 with abdominal pain, weight loss, and jaundice. A pancreatoduodenectomy was carried out, and 3 months later, she presented with a Virchow's node. She was initially treated with cytokines plus 5-fluorouracil derivative, resulting in a complete remission lasting over a year. However, in July 1990, the Virchow's node reappeared and was surgically excised. Histology revealed a small-cell neuroendocrine carcinoma (SCNC) similar to the prior ampullary tumor, which was confirmed by immunohistochemical studies and electron microscopic examination. The patient was discharged within 1 month, remaining disease-free over a 18-month period following excision. We suggest that the use of cytokines can be effective, and can increase survival in gastrointestinal neuroendocrine tumors.


Familial multiple congenital esophageal rings: report of an affected father and son.

Multiple esophageal rings are a very unusual cause of dysphagia. We report a case of a 35-yr-old male with multiple esophageal rings and severe dysphagia, whose father had similar symptoms. Our patient underwent esophageal dilation on one occasion and is asymptomatic at 1-yr followup. We speculate that multiple esophageal rings may be of congenital origin.


Antibiotic-associated fulminant pseudomembranous colitis without toxic megacolon.

Presented is a middle-aged male who developed a fulminant case of antibiotic-associated pseudomembranous colitis characterized by leukocytosis, hypoalbuminemia, ascites, and anasarca without toxic megacolon. The patient responded slowly to medical therapy consisting of intravenous metronidazole, oral vancomycin, and parenteral nutrition. Subsequently, cholestyramine was administered. A review of the literature concerning similar cases of fulminant pseudomembranous colitis is presented.


Syphilitic gastritis in an HIV-infected individual.

We report the first known case of syphilitic gastritis in an HIV-infected person. The presentation of nonspecific abdominal pain and weight loss in a 48-yr-old former intravenous drug user previously treated for asymptomatic syphilis led to a barium swallow which demonstrated linitis plastica. Upper endoscopy reinforced a suspicion of carcinoma, but biopsy made the diagnosis of syphilis by silver staining. Further testing revealed a positive serology for syphilis as well as HIV infection with a depressed CD-4 lymphocyte count. Treatment with parenteral penicillin led to a rapid resolution of symptoms. This case represents a rare complication of late syphilis, and is another example of the unusual manifestations of syphilis seen in the HIV-infected population.


Gastrointestinal obstruction due to Mycobacterium avium intracellulare associated with the acquired immunodeficiency syndrome.

Three patients with the acquired immunodeficiency syndrome (AIDS) had complete or incomplete gastrointestinal obstruction resulting from infection with Mycobacterium avium intracellulare. The pathophysiologic mechanisms of the obstruction in the three cases were ileal volvulus due to adhesions from matted infected mesenteric lymph nodes, ileal intussusception due to engorged infected ileal mucosa, and small bowel displacement and compression by massively enlarged infected intraabdominal lymph nodes. These reports extend the clinical manifestations of Mycobacterium avium intracellulare infection in patients with AIDS to include partial and complete gastrointestinal obstruction.


Arterioportal fistula: a role for pre-TIPSS arteriography and hepatic venous pressure measurements.

A 70-yr-old male presented with massive upper gastrointestinal bleeding secondary to esophageal varices. Because the bleeding was not controlled by sclerotherapy or vasopressin and nitroglycerin, the patient was evaluated for a transjugular intrahepatic portosystemic shunt. Preprocedure arteriography was performed because the etiology of the portal hypertension was uncertain. The arteriogram revealed a hepatic artery to portal vein fistula. Hepatic venous pressure measurements documented an elevated hepatic venous pressure gradient, which diminished dramatically upon embolization of the fistula. Rebleeding from the varices was associated with reestablishment of the fistula via collaterals and elevation of the hepatic venous pressure gradient. The case is presented to establish a role for arteriography prior to transjugular intrahepatic portosystemic shunting, especially in patients with unexplained portal hypertension, and to establish the potential value of hepatic venous pressure measurements in the treatment of arterioportal fistulas.


Delayed massive hemobilia following percutaneous liver biopsy: treatment by embolotherapy.

A patient developed delayed life-threatening hemobilia after apparently uncomplicated percutaneous needle liver biopsy. An arteriobiliary fistula demonstrated by arteriography was successfully treated by selective transcatheter arterial embolization, with Gelfoam and a Gianturco coil. The diagnosis of liver biopsy-induced hemobilia should be suspected when a postprocedure fall in hematocrit is associated with abdominal pain, hyperbilirubinemia, or unexplained gastrointestinal bleeding. A review of the diagnosis and management of liver biopsy-related hemobilia is presented.


Listeria monocytogenes peritonitis: case report and literature review.

Listeria monocytogenes is a Gram-positive bacillus that is pathogenic in both the normal and compromised host. We describe Listeria peritonitis and cerebritis in a patient with cirrhosis due to non-A, non-B hepatitis, and review the 11 other cases of Listeria peritonitis reported in the English-language literature. Listeria is a rare cause of peritonitis in debilitated, older patients, with two-thirds of the cases occurring in patients with chronic liver disease. Listeria peritonitis may also occur in patients undergoing peritoneal dialysis, or in those with malignancy. Peritonitis due to Listeria is clinically similar to spontaneous bacterial peritonitis, and is associated with fever, variable abdominal pain, and neutrocytic ascites; bacteremia commonly accompanies Listeria peritonitis. This syndrome can be successfully treated with antimicrobial drugs, although the third-generation cephalosporins commonly used in the therapy of spontaneous bacterial peritonitis are not recommended. Ampicillin may be the drug of choice, with combination therapy with an aminoglycoside reserved for cases that do not respond to ampicillin alone.


Enterolith ileus: a rare complication of duodenal diverticula.

Small bowel obstruction secondary to an enterolith formed within a duodenal diverticulum is a rare complication. Twenty-nine cases of enterolith ileus have been reported in the literature. This is a case report of the 30th, with review of the literature. Enterolith ileus closely resembles gallstone ileus in its clinical presentation. Diagnosis is established by documenting normalcy of gallbladder and the presence of small bowel diverticula.


Post-cholecystectomy diarrhea: evidence of bile acid malabsorption assessed by SeHCAT test.

Although bile acid malabsorption (BAM) in post-cholecystectomy diarrhea (PCD) is a well-known clinical condition, its true etiopathogenetic role is not entirely clear. The SeHCAT (23-selena-25-homotaurocholic acid) test, a simple and reliable BAM test, was performed in 33 cholecystectomized patients, 26 with chronic diarrhea. The test revealed a marked degree of BAM in 25/26 cases. Cholestyramine in doses of 2-12 g/day was effective in 23/25, ineffective in two, and was not tolerated in one patient. When treatment was suspended, diarrhea recurred in nine, whereas bowel habit remained regular in 60%, with brief sporadic episodes of diarrhea in the other cases. The SeHCAT test was repeated in 11 cases after cholestyramine treatment interruption, and revealed the normalization of parameters in two patients and an improvement in three. We conclude that BAM is an important etiopathogenetic factor in PCD that responds favorably to cholestyramine. In 60% of the cases, it resolved diarrhea definitively, although without eliminating BAM in all cases: this suggests that existence of other factors associated with BAM. The SeHCAT test is essential for a differential diagnosis between PCD and the irritable bowel syndrome.


Marked hyperlipidemia and pancreatitis associated with isotretinoin therapy.

Isotretinoin, a retinoid derivative, is in wide use as a treatment for severe acne and other dermatologic conditions. Its effects on serum lipids, most notably the induction of hypertriglyceridemia, have been well documented. We present a case of a young woman with a previous history of gestational hyperlipidemia who developed hypertriglyceridemia and pancreatitis after initiation of isotretinoin therapy. A history of gestational hyperlipidemia may serve as a marker to help identify patients who are at increased risk for developing severe hypertriglyceridemia while receiving isotretinoin. Her case emphasizes the need to consider the possibility of pancreatitis in patients who develop abdominal pain while receiving this drug.


Multiple hemangiopericytomas of the spleen.

Splenic tumors are uncommon. Described is a 58-yr-old man with multiple hemangiopericytomas of the spleen. Hemangiopericytoma is categorized as a benign vascular tumor, but has a relatively high malignant potential. A review of the literature shows that the case we present is only the second ever reported of a tumor originating from the spleen. Radiological findings and the treatment of the tumor are discussed.


Common bile duct obstruction due to pancreatic involvement in the von Hippel-Lindau syndrome.

Pancreatic involvement in the von Hippel-Lindau syndrome occurs frequently, but is nearly always asymptomatic. Until now, only two cases of bile duct obstruction as a complication of this syndrome have been reported. We present another report of cholestatic jaundice in a patient with the von Hippel-Lindau syndrome and multiple pancreatic cystic lesions, treated by endoscopic implantation of a biliary stent.


Anatomic importance of the retrofacial air tract.

The retrofacial air tract is a constant and relevant anatomic landmark for the temporal bone surgeon. By purposefully dissecting this space, one is able to safely identify the facial nerve, endolymphatic sac, and jugular bulb. The retrofacial air tract also provides access to the petrous apex. Forty temporal bones of varying degrees of pneumatization were dissected in order to study the retrofacial air tract. A well-developed air tract was easily identified in all specimens. We describe our anatomic findings and discuss the surgical relevance and important of the retrofacial air tract.


Binaural cochlear implants.

With the success of monaural cochlear implantation, patients frequently ask about having a second implant. We have performed binaural cochlear implants in 12 adult patients. Desire not to disrupt a functioning implant was the primary consideration in implanting the contralateral ear. Seven patients received a second 3M/House single-channel implant to upgrade to a magnetic external receiver. Four patients with a 3M/House device in one ear elected to place a Nucleus multichannel implant in the opposite ear. One patient with a poorly functioning Nucleus device elected to have a second Nucleus device. Four patients with a Nucleus and a 3M/House implant, one with binaural 3M/House implants, and one with binaural Nucleus implants were tested for auditory discrimination in order to quantify monaural versus binaural differences. The functional benefit of the second implant was mixed, but all patients showed some degree of objective improvement on one or more tests. Five of the six are regular users of both devices; the patient with binaural Nucleus implants wears only one. Despite the differing processing schemes, patients with a Nucleus device in one ear and a 3M/House device in the other ear are able to combine the two signals to advantage. We feel that cochlear implantation in the contralateral ear is an acceptable option in selected patients desiring an upgraded implant without placing a functioning implant at risk.


Macrothrombocytopenia and progressive deafness: a new genetic syndrome.

We report a kindred with hereditary macrothrombocytopenia and progressive sensorineural hearing loss. Although the occurrence of hereditary sensorineural hearing loss associated with macrothrombocytopenia has been reported in a small number of families, varying degrees of renal pathology have always been present. In contrast to the previously reported syndromes involving a giant-platelet disorder and deafness, none of the family members in this report have had any evidence of renal dysfunction. The disorder was inherited in a linear pattern from great-grandmother to grandmother to mother to daughter. The clinical manifestations include hearing impairment that begins before the third decade and progresses to severe to profound bilateral hearing loss by the fourth decade. The platelet disorder manifests in early childhood and persists lifelong, although it tends to remain subclinical. Hematologic and ultrastructural findings will be contrasted to those found in Alport syndrome.


Luetic endolymphatic hydrops: diagnosis and treatment.

Luetic endolymphatic hydrops (LEH) is an effectively treatable disorder that requires astute clinical judgment to suspect, confirm, and treat. We provide a review of the literature as well as recommendations regarding the clinical management of LEH with discussion of several illustrative cases. We also give an overview of laboratory testing for the diagnosis and monitoring of the infectious process. Ultimately, the control of the otologic symptoms in LEH requires acumen on the part of the clinician.


Cochlear implants in the management of bilateral acoustic neuromas.

Multichannel cochlear implants currently provide the only modality for successful auditory rehabilitation of patients with bilateral profound sensorineural hearing loss who derive no benefit from amplification. We have developed a protocol for patients with neurofibromatosis and bilateral acoustic neuromas in which every effort is made to preserve hearing in at least one ear. Failing that, the cochlear nerve is spared, potentially allowing for the insertion of a cochlear implant. We present our data on one such patient whose auditory function was restored with a Nucleus mini 22-channel cochlear implant following removal of his acoustic neuroma.


Evaluation of perilymphatic fistulas by middle ear endoscopy.

Transtympanic endoscopy provides a unique opportunity to view the undisturbed contents of the middle ear. Fiberoptic and rigid endoscopes have been used for thorough examination of the middle ear without the need for local anesthetics or surgical trauma. Endoscopy is now routinely used in the evaluation of a perilymphatic fistula and the patient is awake during an intermittent forceful Valsalva maneuver. Oval and round windows in both ears of five cats were studied endoscopically to evaluate surgically created fistulas. Excellent visualization of the defect was obtained in all instances. Endoscopy is a useful office technique for the evaluation of perilymphatic fistula. It reduces the need for surgical exploration and provides a satisfactory examination of the middle ear. Obliteration of the window niche can even be performed through the myringotomy using autologous blood.


Spontaneous temporal bone cerebrospinal fluid leak.

Eight patients with spontaneous cerebrospinal fluid leak of temporal bone origin are presented. Pertinent history and surgical findings are reviewed and contrasted with 33 previously reported patients. Unilateral ear fullness and mild hearing loss are the most common presenting symptoms. Profuse clear otorrhea following myringotomy is virtually pathognomonic. Diagnostic methods including high-resolution computed tomography, magnetic resonance imaging, and contrast cisternography are discussed. The indications for transmastoid and combined transmastoid/middle fossa surgical repairs are compared. Both surgical approaches were found to be equally effective. We favor the transmastoid as the initial approach because of simplicity, safety, and the ability to visualize both the middle fossa and posterior fossa plates as well as the middle ear.


Autologous fibrin tissue adhesive for ossicular reconstruction in cats.

Autologous fibrin tissue adhesive is currently the most promising adhesive for otologic use with respect to strength and biocompatibility without the risk of transmissable disease that is of concern with the commercially prepared fibrin adhesive. We set out to evaluate the practicality of preparing autologous fibrin adhesive in cats and to see if the adhesive's duration and strength of bonding was sufficient to allow natural tissue union to occur with various grafting materials. Autologous fibrin adhesive was prepared preoperatively from ten cats using the ammonium sulfate precipitation technique. Twenty otologic procedures were performed in which the incus long process was resected and the defect bridged with one of four grafting materials: autograft ossicular bone, bone pate-fibrin glue, porous hydroxylapatite, and Plastipore-bone pate. All grafts were secured with the autologous adhesive. The cats were sacrificed at 6 and 12 weeks. We found the the autologous adhesive provided adequate duration and strength of support to enable a firm tissue union between all the grafting materials and the adjoining incus and stapes.


Ossiculoplasty prognosis: the spite method of assessment.

A series of 535 ossiculoplasties were studied to determine statistically significant links between the presence of presenting preoperative clinical features and adverse audiologic results, in order to identify those aspects of case presentation that indicate a good or poor prognosis. Analysis by chi-square testing has identified twelve features classified as surgical, prosthetic, infection, tissue, and eustachian (SPITE) factors. Regrouping the significant features has demonstrated their value in predicting accurately an ossiculoplasty prognosis. The data were used to compare accurately the results of 247 Plastipore procedures and 265 procedures using the Richards Oval-Top hydroxylapatite implant. There was no statistical difference between the series. The use of these factors will permit precise matching of future series to allow accurate comparisons of prostheses, techniques, individual skills, and also surgical philosophies such as the open and closed cholesteatoma management. Most importantly, the SPITE factors permit an accurate preoperative individual assessment when counseling the patient as to the likelihood of success or failure of a proposed ossiculoplasty.


Beta 2 transferrin application in otology.

The diagnosis and management of perilymphatic fistula has received considerable attention in recent years. Despite the use of sophisticated technology, the diagnosis of perilymphatic fistula continues to rest primarily upon clinical suspicion and the exclusion of other disorders. In addition, the confirmation of a perilymphatic fistula during surgical exploration is usually based upon the subjective observation of fluid pooling in niches of the middle ear. A sensitive and objective laboratory test for identifying perilymph in the middle ear would be a useful adjunct for the diagnosis and management of perilymphatic fistula. The objective of this paper is to demonstrate the potential utility of beta 2 (beta 2) transferrin assay in the diagnosis of perilymphatic fistula. To accomplish this objective, we confirmed that beta 2 transferrin is present in living human perilymph and is absent in the normal or inflamed middle ear. In addition, the utility of beta 2 transferrin assay in the diagnosis of cerebrospinal fluid otorrhea is presented.


Argon laser stapedectomy: comparison to traditional fenestration techniques.

A retrospective review of all stapedectomies performed at the Massachusetts Eye and Ear Infirmary over a 13 month period was undertaken to compare the results of argon laser stapedectomy to conventional footplate fenestration techniques. Despite the fact that it was new and unfamiliar to the surgical staff, the complication rate was lower with the argon laser than with footplate fenestration by traditional pick or drill techniques. The incidence of footplate fracture or removal preventing use of a small fenestra technique was five times as likely to occur with traditional instruments as with the argon laser (p < 0.025). In revision stapedectomy sensorineural hearing loss was four times as likely to occur with traditional instruments as with the argon laser (p < or = 0.05). The argon laser did not alter the operating time. Though not ideal for every case, the argon laser endo-otoprobe offers the surgeon a significant new tool to improve the outcome in stapes surgery.


Radiographic differential diagnosis of petrous apex lesions.

As a consequence of improved diagnostic imaging modalities, otologists have encountered a steadily increasing number of petrous apex lesions in recent years. Contemporary imaging techniques not only provide precise anatomic localization of the lesion, but also are able to suggest specific tissue diagnoses in the majority of cases. Computed tomography (CT), by virtue of its sensitivity and low false-positive rate, is the screening examination of choice in a patient suspected of having a petrous apex lesion. Once a lesion is identified, it is often necessary to obtain a combination of CT and magnetic resonance imaging (MRI). Computed tomography is important in the detection of osseous erosion as well as in the evaluation of the extent of pneumatization and marrow formation. It also provides important details about potential surgical routes to this relatively inaccessible region. Magnetic resonance imaging provides information about the composition of the lesion that cannot be readily discerned on CT scans. In the great majority of cases, it is capable of differentiating between petrous apicitis, cholesterol granuloma, osteomyelitis, cholesteatoma, and neoplasms such as schwannoma, meningioma, chondroma, and chordoma. In the interpretation of MRI scans, a familiarity with the typical appearance of the lesions that affect the petrous apex on T1-weighted, T2-weighted, and gadolinium-enhanced images is essential. A combination of MRI and CT scanning is also necessary to evaluate normal anatomic variations, such as giant air cells and asymmetric bone marrow, which may at times, on MRI alone, simulate pathologic conditions.