Hyperspectral data processing improves PpIX contrast during fluorescence guided surgery of human brain tumors.

Fluorescence guided surgery (FGS) using aminolevulinic-acid (ALA) induced protoporphyrin IX (PpIX) provides intraoperative visual contrast between normal and malignant tissue during resection of high grade gliomas. However, maps of the PpIX biodistribution within the surgical field based on either visual perception or the raw fluorescence emissions can be masked by background signals or distorted by variations in tissue optical properties. This study evaluates the impact of algorithmic processing of hyperspectral imaging acquisitions on the sensitivity and contrast of PpIX maps. Measurements in tissue-simulating phantoms showed that (I) spectral fitting enhanced PpIX sensitivity compared with visible or integrated fluorescence, (II) confidence-filtering automatically determined the lower limit of detection based on the strength of the PpIX spectral signature in the collected emission spectrum (0.014-0.041 µg/ml in phantoms), and (III) optical-property corrected PpIX estimates were more highly correlated with independent probe measurements (r = 0.98) than with spectral fitting alone (r = 0.91) or integrated fluorescence (r = 0.82). Application to in vivo case examples from clinical neurosurgeries revealed changes to the localization and contrast of PpIX maps, making concentrations accessible that were not visually apparent. Adoption of these methods has the potential to maintain sensitive and accurate visualization of PpIX contrast over the course of surgery.

A phase II trial of temozolomide for patients with recurrent or progressive brain metastases.

BACKGROUND: Treatment options for patients with recurrent brain metastases are extremely limited. This study was designed to determine the safety and efficacy of temozolomide in the treatment of recurrent or progressive brain metastases. PATIENTS AND METHODS: Forty-one patients (11 men, 30 women) with a median KPS of 80 were treated with temozolomide 150 mg/m2/day (200 mg/m3/day if no prior chemotherapy) for 5 days; treatment cycles were repeated every 28 days. Primary tumor types included 22 non-small cell lung, 10 breast, three melanoma, two small cell lung, two rectal, one ovarian and one endometrial cancer. RESULTS: There were five episodes of grade 3 thrombocytopenia and one grade 4 leukopenia. Significant non-hematologic toxicity possibly related to temozolomide included pneumonitis [21, constipation [1], and elevated liver enzymes [21. Thirty-four patients were assessed for radiographic response; two had a partial response, 15 stable disease and 17 progressed. Both objective responses were seen in patients with non-small cell lung cancer. Overall median survival was 6.6 months. CONCLUSIONS: Single agent temozolomide achieved disease control (PR or SD) in 41% of patients with recurrent brain metastases from a variety of primary malignancies with minimal toxicity. Therefore, temozolomide may be a reasonable treatment option for some patients with recurrent brain metastases.

Inhibition of human platelet function by sulfatides.

Sulfatides are glycolipid constituents of human platelet cell membranes and have been shown to interact with platelet-binding proteins involved in hemostasis. Because little is known about the physiological role of sulfatides in platelet function, the effect of sulfatide on platelet adhesion, aggregation, release, and ristocetin-induced platelet agglutination (RIPA) was studied. These processes are inhibited when exogenous sulfatide is present in vitro. Inhibition of aggregation induced by collagen, thrombin, and ristocetin by sulfatide was dose dependent. Adenosine diphosphate-mediated adhesion and aggregation were not significantly affected by sulfatide, nor was serotonin- and epinephrine-mediated aggregation. Collagen mediate release of serotonin was reduced sulfatide. RIPA demonstrated dose-dependent inhibition in response to sulfatide. These results suggest that sulfatide may play a role in modulating platelet activation.

Long-term outcome of low-grade oligodendroglioma and mixed glioma.

BACKGROUND: Low-grade oligodendrogliomas and mixed gliomas can be indolent and remain unchanged for years. Optimal timing and effectiveness of initial treatment is uncertain and therapy can be associated with toxicity. METHODS: Retrospective review of patients diagnosed between 1979 and 1997 with low-grade oligodendroglioma or mixed glioma. Time to progression, survival, prognostic factors, and treatment toxicities were evaluated. RESULTS: A total of 106 patients (77 oligodendroglioma, 29 mixed glioma) were identified; median age was 36.7 years. Initial presenting symptoms were seizures in 76 (72%) and headache in 11 (10%); tumor was diagnosed as an incidental finding in five patients. Tumor progression was diagnosed in 72 patients (68%). Overall median time to progression (MTTP) was 5.0 years (range 0.5 to 14.2). Median overall survival (OS) was 16.7 years. No prognostic factors reached statistical significance. MTTP and OS were not significantly affected by treatment. Of 62 patients who received radiation therapy, 9 (15%) developed radiation necrosis and 13 developed radiation therapy-related cognitive changes, requiring ventriculoperitoneal shunting in six. Significant myelosuppression was seen in 35 of 76 (46%) patients treated with chemotherapy. CONCLUSIONS: Low-grade oligodendroglioma and mixed glioma have a long median overall survival. There were no apparent differences in either immediate versus deferred treatment or choice of initial therapy on disease-free or overall survival. Chemotherapy was associated with significant acute toxicity in almost one half of patients; radiation therapy produced late neurotoxicity in one third, justifying deferred treatment until clinically necessary.

Fetal hemorrhage and platelet dysfunction in SLP-76-deficient mice.

The adapter protein SLP-76 is expressed in T lymphocytes and hematopoietic cells of the myeloid lineage, and is known to be a substrate of the protein tyrosine kinases that are activated after ligation of the T-cell antigen receptor. Transient overexpression of SLP-76 in a T-cell line potentiates transcriptional activation after T-cell receptor ligation, while loss of SLP-76 expression abrogates several T-cell receptor-dependent signaling pathways. Mutant mice that lack SLP-76 manifest a severe block at an early stage of thymocyte development, implicating SLP-76 in signaling events that promote thymocyte maturation. While it is clear that SLP-76 plays a key role in development and activation of T lymphocytes, relatively little is understood regarding its role in transducing signals initiated after receptor ligation in other hematopoietic cell types. In this report, we describe fetal hemorrhage and perinatal mortality in SLP-76-deficient mice. Although megakaryocyte and platelet development proceeds normally in the absence of SLP-76, collagen-induced platelet aggregation and granule release is markedly impaired. Furthermore, treatment of SLP-76-deficient platelets with collagen fails to elicit tyrosine phosphorylation of phospholipase C-gamma2 (PLC-gamma2), suggesting that SLP-76 functions upstream of PLC-gamma2 activation. These data provide one potential mechanism for the fetal hemorrhage observed in SLP-76-deficient mice and reveal that SLP-76 expression is required for optimal receptor-mediated signal transduction in platelets as well as T lymphocytes.

The Collaborative Hospital Transfusion Study: variations in use of autologous blood account for hospital differences in red cell use during primary hip and knee surgery.

BACKGROUND: Red cell use in patients undergoing Diagnosis Related Group (DRG) 209 procedures (major joint and limb reconstruction procedures of the lower extremities) has been shown to have large, unexplained interhospital variations. STUDY DESIGN AND METHODS: Abstracted records of 2590 consecutive DRG 209 patients at five university hospitals from January 1992 to December 1993 were stratified by procedure and preoperative blood deposit status. Patient characteristics and transfusion and in-hospital outcomes were compared across hospitals. RESULTS: Blood use among patients who did not preoperatively deposit blood was similar across hospitals. Significant differences were found across hospitals for total hip replacement patients in the percentage of patients preoperatively depositing blood (59-80%), percentage of patients receiving transfusion(s) (51 to > 99%), the mean number of units collected per patient (1.6-2.9), and the mean number of unused autologous units per 100 patients (1-185). No significant differences were found in the percentage of those who deposited blood and then required allogeneic units. There was little variability in length of hospital stay or in last hematocrits. Findings were similar for total knee replacement patients. CONCLUSIONS: Interhospital variations in red cell use for primary total hip and knee reconstruction are primarily due to hospital-specific differences in autologous blood collection and transfusion.

The specific hospital significantly affects red cell and component transfusion practice in coronary artery bypass graft surgery: a study of five hospitals.

BACKGROUND: Interhospital differences in blood transfusion practice during coronary artery bypass graft (CABG) surgery have been noted, but the underlying issues have not been identified. STUDY DESIGN AND METHODS: Records of 3217 consecutive CABG cases in five university teaching hospitals in 1992 and 1993 were stratified by hospital, type of revascularization conduit, patients' sex, and other factors. Statistical methods were used to compare patient characteristics, transfusion outcomes, and hospital outcomes. RESULTS: Forward two-step logistic regression using patient likelihood of red cell transfusion factors in the first step and the specific hospital in the second step revealed a significant effect of hospital on the delta odds ratios for red cell transfusion. This finding was confirmed by analyses of a highly stratified subset of cases, males in diagnosis-related group 107 (primary cases of coronary bypass without coronary catheterization) who underwent revascularization with venous and internal mammary artery grafts, revealing variations among hospitals from 109 to 457 units of red cells transfused per hundred cases. Corresponding variations in transfusions of all blood components were from 324 to 1019 units by hospital. Variation in red cell transfusion practice among surgeons in the same hospital was not responsible for these interhospital differences. CONCLUSION: The effect of the specific hospital on transfusion practice is attributed to institutional differences that, through reasons of training or hierarchy, become ingrained in hospitals.

Determinants of red cell, platelet, plasma, and cryoprecipitate transfusions during coronary artery bypass graft surgery: the Collaborative Hospital Transfusion Study.

BACKGROUND: Very little is known about the determinants of blood transfusions in patients undergoing coronary artery bypass graft surgery. STUDY DESIGN AND METHODS: To identify factors that influenced the transfusion of red cells, platelets, plasma, and cryoprecipitate, statistical methods were used to study 2476 consecutive diagnosis-related group 106 and 107 patients in five teaching hospitals who underwent coronary artery bypass surgery between January 1, 1992, and June 30, 1993. RESULTS: The likelihood of red cell transfusion was significantly associated with 10 preoperative factors: 1) admission hematocrit, 2) the patient's age, 3) the patient's gender, 4) previous coronary artery bypass surgery, 5) active tobacco use, 6) catheterization during the same admission, 7) coagulation defects, 8) insulin-dependent diabetes with renal or circulatory manifestations, 9) first treatment of new episode of transmural myocardial infarction, and 10) severe clinical complications. Platelet and/or plasma transfusions were strongly associated with the dose of red cells transfused. Transfusion requirements and other in-hospital outcomes were associated with patient characteristics, surgical procedure (reoperation vs. primary procedure), and the conduits used for revascularization (venous graft only, venous and internal mammary artery graft, or internal mammary artery graft only). Blood resource use and donor exposures were evaluated with respect to the risk to patients of contracting hepatitis C virus and human immunodeficiency virus infections. CONCLUSION: The classification of coronary artery bypass graft patients on the basis of attributes known preoperatively and by conduits used yields subsets of patients with distinctly different transfusion requirements and in-hospital outcomes.

Analysis of changes in coagulation factors after postoperative blood loss in burn and non-burn patients.

A prospective study of the postoperative kinetics of coagulation factors was undertaken in 23 burn patients and in six non-burn patients. All procedures resulted in a large volume blood loss. Fibrinogen, platelets and factors V, VIII and IX were measured serially. Burn patients returned all parameters to preoperative levels by 48 h postoperation, while non-burn patients showed a slower rate of return of platelets and factor V. This study suggests that burn patients may safely undergo re-operation at 48 h intervals for successive wound debridements if clinically necessary.

Isolated right atrial tamponade after open heart surgery: role of echocardiography in diagnosis and management.

Ten patients with isolated right atrial tamponade complicating open heart surgery were identified over a 3.5-year period at three institutions. Clinical manifestations varied but were typically those of decreased perfusion with elevated central venous pressure. Hemodynamically these patients had systemic hypotension and tachycardia with elevated central venous pressure but without elevation of pulmonary artery or pulmonary artery wedge pressures. The correct diagnosis in each case was established by echocardiography; 7 via the transthoracic and 3 via the transesophageal approach. The typical echocardiographic feature was an extrinsic extracardiac mass compressing the atrium. Doppler findings included high flow velocities through the right atria, and color flow demonstrated narrow color jets through compressed, slit-like right atria. Surgical exploration confirmed these findings in each case. We conclude that the combination of clinical awareness and appropriate hemodynamic evaluation can alert the physician to the possibility of isolated right atrial hematoma causing decreased perfusion and/or shock following open heart surgery. Echocardiography using either the transthoracic or transesophageal approach can establish the diagnosis and lead to timely surgical intervention.

Monoclonal antibodies to platelet glycoproteins Ib and IIb/IIIa inhibit adhesion of platelets to purified solid-phase von Willebrand factor.

Platelet membrane glycoproteins Ib (GPIb) and IIb/IIIa (GPIIb/IIIa) bind soluble von Willebrand factor (vWf) after stimulation with ristocetin (GPIb) or with thrombin or ADP (GPIIb/IIIa). In fluid-phase, vWf does not bind to these platelet receptors without stimulation. In contrast, platelets adhere to solid-phase vWf without stimulation by ristocetin, adenosine diphosphate (ADP), or thrombin, and adhesion increases after stimulation by these agonists. The effect of monoclonal antibodies specific for GPIb (6D1) and GPIIb/IIIa (10E5 and HP1-1D) on platelet adhesion to solid-phase vWF was studied. Adhesion of radiolabeled, washed platelets (with washed red blood cells) aspirated at a constant wall shear rate of 1000 sec-1 through glass capillary tubes coated with purified human vWf was quantified. Unstimulated platelet adhesion was decreased 80% to 90% by blocking either the GPIb site or the GPIIb/IIIa site with 6D1 or 10E5, respectively, or with 6D1 and 10E5 together. Adhesion was not reduced significantly by HP1-1D (anti-GPIIb/IIIa). After stimulation with ADP or thrombin, the platelet adhesion was reduced by prior incubation with saturating concentrations of either 6D1 (61% reduction) or 10E5 (80% reduction), as well as with both 6D1 and 10E5 (80% reduction). After stimulation with ristocetin, the adhesion was reduced with either 6D1 (90% reduction) or 10E5 (90% reduction) or both 6D1 and 10E5 (90% reduction). Prior incubation with HP1-1D had minimal effect on platelet adhesion to vWF after stimulation with thrombin, ADP, or ristocetin.(ABSTRACT TRUNCATED AT 250 WORDS)

Cytokine and complement levels in patients undergoing cardiopulmonary bypass.

Patients undergoing cardiopulmonary bypass are known to develop whole body inflammation that often results in a characteristic syndrome early postoperatively. This phenomenon has been attributed to complement activation caused by exposure of blood to the foreign surfaces of the cardiopulmonary bypass circuit. It has been unknown if cytokines are involved. Plasma levels of complement activation products (C3a, C4a, C5a, and C5b-9), interleukins (IL-1 beta, IL-2, IL-4, and IL-6), and tumor necrosis factor-alpha were measured at multiple time points before, during, and after cardiopulmonary bypass in 29 patients. No significant increase over preinduction levels was seen in the cytokines except for IL-6, which was significantly increased during cardiopulmonary bypass (p < 0.001), reaching a maximum 3 hours after cardiopulmonary bypass. C3a, C4a, and C5b-9 levels were significantly elevated during cardiopulmonary bypass (p < 0.001), with maximum C5b-9 levels preceding the IL-6 elevation. Heparin coating of the cardiopulmonary bypass circuit was not demonstrated to have an effect on activation of complement or cytokine production. There was no statistically significant correlation among hemodynamic variables or pulmonary function and complement, interleukin, or tumor necrosis factor-alpha levels. These results confirm the presence of complement activation and demonstrate the production of IL-6 after the generation of C5b-9 in patients undergoing cardiopulmonary bypass. IL-6 may contribute to adverse systemic reactions associated with cardiopulmonary bypass.

Endoscopic carpal tunnel release: a comparison of two techniques with open release.

Proponents of endoscopic carpal tunnel release claim less pain and scar tenderness, quicker recovery of strength, and earlier return to work and daily activities over open methods to release the transverse carpal ligament. This single-center prospective study is the first to compare three different treatment methods: standard open release, a single-portal endoscopic technique (Agee), and a two-portal endoscopic technique (Chow). Two hundred eleven releases in 163 patients were evaluated by clinical outcomes questionnaire and objective testing over a 6-month follow-up period. There was no difference in resolution of paresthesias or nocturnal pain between treatment methods. Patients treated with open release reported more thumb weakness and pain with activities of daily living after surgery. Endoscopically treated patients achieved faster recovery of grip and pinch strength and wrist range of motion. Patients treated endoscopically had less mid-palm tenderness than did patients treated via the open technique, and Agee patients had less distal palmar tenderness than did patients treated via other methods. Overall, and in the workers' compensation group, patients treated endoscopically returned to work sooner. In the non-workers' compensation group, Agree patients returned to work sooner than did patients treated via the other two methods.

Torsion of the gallbladder. A review of four cases.

Four cases of torsion of the gallbladder have been gathered from this area. Three were admitted to our local hospitals and the fourth case occurred in the Veteran's Hospital in Fayetteville. The average age of these four cases was 85, and all patients were very thin. Three patients were female and one was male. One patient died following surgery. This patient had sought help rather late, and died of cardiopulmonary complications. This entity is rare, and only scattered cases are found in the literature. Biliary calculi are found in approximately 50% of the cases. The exact etiology of the torsion is unknown. A redundant mesentery is always present, and kyphosis is frequent. Our patients were all thin. Botha has postulated that vigorous peristalsis in the neighboring viscera or sudden body movement may be responsible. The diagnosis is rarely made preoperatively, but if surgery is not done, death will probably ensue. Later reports have indicated that sonography and abdominal CT scanning might prove helpful in establishing a diagnosis.

An early case of the Zollinger-Ellison syndrome produced by a carcinoid tumor of the duodenum.

We have reported a case of Zollinger-Ellison Syndrome which proved to be due to a small carcinoid tumor of the wall of the duodenum. At the time that this was found, I could not find any such cases in the literature. In talking with Dr. Ellison personally, it was my impression that he was probably not aware of this syndrome. There are relatively few cases in the literature, and in a report by Dr. Van Heerden, et al from the Mayo Clinic, of 154 patients with carcinoid tumors of the GI tract, there were only two cases of the carcinoid tumor found the duodenum. One had a gastrin producing tumor 1 cm in diameter with positive nodes which was excised locally, and the patient was alive and well and not taking medication after 10 years. In this case, I think that serendipity played a great part, because I had no knowledge of the relation between the carcinoid tumor and the severe ulcer diathesis it produced.

Exclusion of atrial thrombus by transesophageal echocardiography.

To determine whether transesophageal echocardiography (TEE) is useful in ruling out the presence of atrial thrombus, we performed TEE in 20 patients immediately before valve replacement or valve repair and within 3 days of an autopsy in one patient. Mitral stenosis was the predominant lesion in three patients, mitral regurgitation was seen in 11 patients, five patients had mitral prosthesis malfunction, one patient had a tricuspid prosthesis malfunction, and one patient had aortic stenosis. Eight patients were in atrial fibrillation. Four patients demonstrated spontaneous contrast in the associated atria. Nine patients were receiving oral anticoagulation. Mean left atrial diameter was 5.3 +/- 1.3 mm. TEE revealed no evidence for atrial thrombus in 18 of the 21 patients; this finding was confirmed by careful inspection of the atria including the appendages. TEE demonstrated a left atrial thrombus in two patients and a right atrial thrombus in another (confirmed at the time of surgery or at autopsy). In all cases transthoracic echocardiography was negative. Our data suggest that TEE is useful in ruling out atrial thrombus, and therefore may be a useful test preceding interventions associated with an increased risk of embolism from the atria such as cardioversion, mitral valvuloplasty, or valve replacement.

Transesophageal echocardiography in patients with mechanical circulatory assistance.

Transesophageal echocardiography was used to assess myocardial function and to detect complications after mechanical circulatory support for 8 patients with cardiogenic shock. In 3 of 8 patients, serial transesophageal echocardiography documented improvement of systolic ventricular function, and it was possible to wean these 3 patients from the ventricular assist device. In all patients, transesophageal echocardiography added clinically important information including the extent of left and right ventricular dysfunction (6 patients), presence of atrial or ventricular thrombus (5 patients), presence of pericardial effusion or clot (2 patients), and verification of the position of the intravascular device (1 patient). Thus, transesophageal echocardiography may provide clinically useful information regarding both the underlying cardiac disease and potential complications from the mechanical circulatory assistance.

Isolation and characterization of an acquired antithrombin antibody.

A 68-year-old man, following mitral valve replacement, presented with a low-grade chronic consumptive coagulopathy. Laboratory analysis showed mild fibrinolysis, minimal effect of coumadin therapy, and a prolonged thrombin time (greater than 150 seconds using bovine IIa). When purified human IIa was used the thrombin time normalized to within 17 seconds of controls, suggesting a possible inhibitor of bovine IIa. An anti-IIa antibody was isolated by protein A-Sepharose (Sigma, St Louis, MO) chromatography followed by affinity chromatography using a bovine IIa-Sepharose column. The effects of this purified anti-IIa antibody on both bovine and human IIa procoagulant and anticoagulant functions were studied. The isolated immunoglobulin G (IgG) was observed to inhibit bovine IIa in all assays tested. This IgG was also able to slightly prolong fibrinogen clotting by human IIa. Using an enzyme-linked immunosorbent assay it was observed that the IgG bound to bovine IIa, bovine II, human IIa, but not to human II. Further, binding was detectable at approximately 50-fold lower concentrations to bovine IIa (1 nmol/L IgG concentration) than to human IIa (50 nmol/L IgG concentration). The effect of the antibody on the reaction between IIa and AT III/heparin was investigated. Human IIa was found to be protected from AT III/heparin neutralization in the presence of this antibody. These results suggest that this patient developed an antibody that strongly binds to and inhibits the bovine IIa in all assays tested. However, the antibody only significantly affects human IIa neutralization by AT III/heparin, and has little effect on the human IIa procoagulant activity. These data suggest that the decreased effect of AT III/heparin on this patient's IIa may have been a contributing factor in his coagulopathy. The exact cause of this antibody development is unclear, but the role of bovine topical thrombin used during cardiac valve replacement surgery is suspect.

Effects of androgenizing dairy heifers with ear implants containing testosterone and estrogen on detection of estrus.

Lactating dairy cows in four lots were observed for sexual behavior for 6 mo. One freemartin heifer in each lot was implanted with testosterone propionate and estradiol benzoate to aid in detection of estrus. Blood samples were obtained from androgenized heifers every other week for determination of serum testosterone. The addition of an androgenized heifer to each lot increased the number of mounts and attempts to mount cows, both overall and within observation periods. Thus, the likelihood of detecting a cow in estrus was increased with the addition of the androgenized heifers. Greatest benefit was seen when one or two cows were simultaneously in estrus in each lot. Observational data and serum progesterone concentration of mounted cows indicated that androgenized heifers were selectively mounting open cows displaying estrus, whereas the remaining nonandrogenized cows were less selective with their mounting activity. Serum testosterone increased after heifers were implanted, but testosterone was not related to the proportion of sexual activity. Duration of sexual activity by the implanted heifers was approximately 90 d.