Novel Therapies in Olfactory Disorders.

Purpose of Review: To summarize and critically review the recent literature on novel treatments for olfactory disorders (OD). Recent Findings: Emerging therapies in the management of OD include multiple vitamins and supplements, biologics, neuromodulators, and intranasal agents. There is also an active investigation into treatments that harness the neuroregenerative properties of the olfactory epithelium, such as platelet-rich plasma and stem cell transplantation. Summary: Successful management of OD is multimodal and tailored to the underlying etiology. As the findings of further investigations accrue, the management of OD will undoubtedly continue to be advanced and refined, and likely harness the intrinsic neuroregenerative properties of the olfactory system.

Hemodynamic changes in patients undergoing office-based sinus procedures under local anesthesia.

BACKGROUND: The objective of this study is to characterize changes in hemodynamics, pain, and anxiety during office-based endoscopic sinus procedures performed under local anesthesia. METHODS: We conducted a prospective study of adults undergoing in-office endoscopic sinus procedures under local anesthesia. Patients with American Society of Anesthesiologists (ASA) Physical Status Classification System class 1 or 2 were included. Anesthesia was administered by topical 4% lidocaine/oxymetazoline and submucosal injection of 1% lidocaine/1:200,000 epinephrine. Vital signs and pain were measured at baseline, postinjection, and 5-minute intervals throughout the procedure. Anxiety levels were scored using the State-Trait Anxiety Inventory (STAI). Univariate and multivariate regression analyses were performed to identify factors significantly associated with changes in each hemodynamic metric. RESULTS: Twenty-five patients were studied. This cohort was 52% male, mean age of 57.8 ± 14.4 years, and Charlson Comorbidity Index (CCI) median of 2. Mean procedure duration was 25.0 ± 10.3 minutes. Mean maximal increase in systolic blood pressure (SBP) was 24.6 ± 17.8 mmHg from baseline. Mean maximal heart rate increase was 22.8 ± 10.8 beats per minute (bpm) from baseline. In multivariate regression analysis, when accounting for patient age, cardiac comorbidity, CCI, and ASA, older age was significantly associated with an increase of >20 mmHg in SBP (p = 0.043). Mean pain score during procedures was 1.5 ± 1.3 with a mean maximum of 4.0 ± 2.6. STAI anxiety scores did not change significantly from preprocedure to postprocedure (32.8 ± 11.6 to 31.0 ± 12.6, p = 0.46). No medical complications occurred. CONCLUSION: Although patients appear to tolerate office procedures well, providers should recognize the potential for significant fluctuations in blood pressure during the procedure, especially in older patients.

Circumscribed Choroidal Hemangioma: Visual Outcome in the Pre-Photodynamic Therapy Era versus Photodynamic Therapy Era in 458 Cases.

PURPOSE: To analyze visual outcomes after treatment of choroidal hemangioma in the pre-photodynamic therapy (PDT) era versus PDT era. DESIGN: Retrospective, comparative case series. PARTICIPANTS: A total of 458 patients with circumscribed choroidal hemangioma. METHODS: Comparison of hemangioma managed in the pre-PDT (1967-2001) era versus PDT (2002-2018) era. MAIN OUTCOME MEASURE: Visual acuity outcome. RESULTS: A total of 458 tumors were treated over this 51-year period. A comparison (pre-PDT [n = 220 cases] vs. PDT [n = 238 cases]) revealed PDT era patients were of older mean age (48.9 vs. 53.8 years, P = 0.002) and were more likely to have systemic hypertension (17.7% vs. 33.8%, P < 0.001), tumor location in the macula (57.4% vs. 67.5%, P = 0.01), subretinal fluid on OCT (33.3% vs. 70.7%, P = 0.01), and greater extent of overlying lipofuscin (P = 0.001). Findings of tumor basal diameter and thickness and fluorescein and indocyanine green angiography were no different in the 2 eras. Treatment (pre-PDT vs. PDT) included argon laser photocoagulation (42.1% vs. 0.4%), PDT (0% vs. 43.8%), transpupillary thermotherapy (0% vs. 0.4%), plaque radiotherapy (7.0% vs. 5.2%), external beam radiotherapy (1.4% vs. 1.3%), enucleation (0.9% vs. 0.4%), and observation (48.6% vs. 47.6%). After treatment, patients in the PDT era demonstrated better mean logarithm of the minimum angle of resolution visual acuity (1.28 vs. 0.51, P < 0.001) (Snellen equivalent 20/400 vs. 20/63, P < 0.001). Final visual acuity was ≥20/40 for those with entering vision of ≥20/40 (59.6% vs. 74.7%, P = 0.001) and for those with entering vision of 20/50-20/200 (25.4% vs. 47.3%, P < 0.001). CONCLUSIONS: Management of choroidal hemangioma in the PDT era has allowed for significantly better visual outcome compared with the pre-PDT era, with mean final visual acuity of 20/400 (pre-PDT era) versus 20/63 (PDT era).

Alanine Aminotransferase Results Differ by Analyzer Manufacturer in a National Integrated Health Setting, 2012-2017.

CONTEXT.­: Disease guidelines specify universal alanine aminotransferase (ALT) thresholds for clinical decision-making, yet the effect of variability among ALT analyzers remains unclear. OBJECTIVE.­: To compare ALT results from different analyzers from 2012-2017. DESIGN.­: Veterans Health Administration (VHA) laboratories perform external ALT proficiency testing using standardized College of American Pathologists (CAP) samples in analyzers by 5 manufacturers. In this operational analysis, we evaluated 22 950 ALT values from 80 independent CAP samples tested at 223 laboratories. Using mixed effects modeling, we estimated the association between analyzer manufacturer and CAP outcome, adjusting for manufacturer, facility, and calendar year. We performed subgroup analyses on CAP samples with overall means near clinical guideline-specified thresholds, including less than 50 U/L (n = 10) and less than 35 U/L (n = 5). RESULTS.­: The VHA used Abbott Laboratories (n = 3175; 14%), Beckman Coulter Diagnostics (n = 8723; 38%), Roche Diagnostics (n = 2595; 11%), Siemens Healthineers USA (n = 5713; 25%), and Vitros/Ortho Clinical Diagnostics (n = 2744; 12%) analyzers. The CAP samples (n = 80 samples, n = 22 950 tests) covered a wide range of mean ALT values (21-268 U/L). The average difference in mean ALT value per sample between the highest-reading and lowest-reading manufacturers was 15.4 U/L (SD = 1.8) for the 10 samples with mean ALT less than 50 U/L, and it was 10.4 U/L (SD = 3.6) overall (n = 80). In linear mixed effects modeling, we found statistically significant differences in ALT values between the different manufacturers in each year. CONCLUSIONS.­: We found statistically and clinically meaningful differences between analyzers across the ALT spectrum in each year, including at ALT levels lower than 50 U/L and lower than 35 U/L. Universal ALT thresholds should be avoided as a trigger for clinical action until differences between analyzers can be resolved.

Cryosurgical ablation for treatment of rhinitis: A prospective multicenter study.

OBJECTIVE: To assess the efficacy and safety of cryoablation of the posterior nasal nerve (PNN) for treatment of chronic rhinitis. METHODS: This was a prospective single-arm trial of 98 adult patients at six U.S. centers with chronic allergic and nonallergic rhinitis. PNN cryoablation was performed in-office under local anesthesia using a handheld device. Patients discontinued use of intranasal ipratropium 3 days prior to treatment and throughout the study period. Reflective Total Nasal Symptom Score (rTNSS) was measured at pretreatment baseline and posttreatment at 1 month, 3 months, 6 months, and 9 months. The Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) was completed at pretreatment and 3 months posttreatment. Adverse effects and postprocedure medication usage were recorded. RESULTS: Ninety-eight procedures (100%) were successfully completed. rTNSS significantly improved over pretreatment baseline (6.1 ± 1.9) at 1 month (2.9 ± 1.9, P < 0.001), 3 months (3.0 ± 2.3, P < 0.001), 6 months (3.0 ± 2.1, P < 0.001), and 9 months (3.0 ± 2.4, P < 0.001) postprocedure. Nasal congestion and rhinorrhea subscores improved significantly at all time points (P < 0.001). Both allergic and nonallergic rhinitis subcohorts showed improvement (P < 0.001), with a comparable degree of improvement between groups. RQLQ significantly improved over pretreatment baseline (3.0 ± 1.0) at 3 months (1.5 ± 1.0, P < 0.001), and all RQLQ subdomains demonstrated improvement. Of 54 patients using intranasal medication at baseline, 19 (35.2%) were able to discontinue use. Twenty-nine adverse effects were reported, including headache, epistaxis, and sinusitis. CONCLUSION: Cryoablation of the PNN for chronic rhinitis is safe and can result in relief of nasal symptoms and improvements in quality of life. LEVEL OF EVIDENCE: 4 Laryngoscope, 130: 1877-1884, 2020.

Nomogram for visual acuity outcome after iodine-125 plaque radiotherapy and prophylactic intravitreal bevacizumab for uveal melanoma in 1131 patients.

AIMS: To develop a nomogram for prediction of visual acuity outcome following plaque radiotherapy for uveal melanoma. METHODS: Retrospective review of uveal melanoma treated with plaque radiotherapy and prophylactic intravitreal bevacizumab injections at 4-month intervals for 2 years duration. Two nomograms for poor visual acuity outcome (Snellen <20/200) were developed based on (1) Clinical risk factors. (2) Or clinical and treatment risk factors. RESULTS: There were 1131 included cases. The most important clinical risk factors (points for nomogram) for poor visual acuity outcome included subretinal fluid involving four quadrants (100), tumour thickness >4 mm (69), presenting visual acuity ≤20/30 (65), non-Caucasian race (58), tumour shape mushroom, bilobed, or multilobulated (57), and insulin-dependent diabetes (54). Risk of poor visual acuity at 2 years and 4 years increased from 11% and 24% with 40 points to 97% and >99% with 304 points. A second analysis was performed using both clinical and treatment risk factors. The most important factors included presenting visual acuity ≤20/30 (100), tumour largest basal diameter >11 mm (80), radiation dose rate to tumour base ≥164 cGy/hour (78), tumour thickness >4 mm (76), insulin-dependent diabetes (75) and abnormal foveolar status by optical coherence tomography at presentation (72). Risk of poor visual acuity at 2 years and 4 years increased from 6% and 14% with 56 points to 88% and 99% with 496 points. CONCLUSIONS: A nomogram using clinical or treatment risk factors can predict visual acuity outcome following plaque radiotherapy and prophylactic intravitreal bevacizumab for uveal melanoma and is available online at https://fighteyecancer.com/nomograms/.

Arbitrary-Waveform Electro-Optical Intracranial Neurostimulator With Load-Adaptive High-Voltage Compliance.

A hybrid 16-channel current-mode and the 8-channel optical implantable neurostimulating system is presented. The system generates arbitrary-waveform charge-balanced current-mode electrical pulses with an amplitude ranging from 50 [Formula: see text] to 10 mA. An impedance monitoring feedback loop is employed to automatically adjust the supply voltage, yielding a load-optimized power dissipation. The 8-channel optical stimulator drives an array of LEDs, each with a maximum of 25 mA current amplitude, and reuses the arbitrary-waveform generation function of the electrical stimulator. The LEDs are assembled within a custom-made 4×4 ECoG grid electrode array, enabling precise optical stimulation of neurons with a 300 [Formula: see text] pitch between the LEDs and simultaneous monitoring of the neural response by the ECoG electrode, at different distances of the stimulation site. The hybrid stimulation system is implemented on a mini-PCB, and receives power and stimulation commands inductively through a second board and a coil stacked on top of it. The entire system is sized at 3×2 . 5×1 cm3 and weighs 7 grams. The system efficacy for electrical and optical stimulation is validated in-vivo using separate chronic and acute experiments.

Retrograde parotidectomy under local anesthesia for benign, malignant, and inflammatory lesions.

OBJECTIVE: To report the patient selection, surgical technique, and outcomes of parotidectomy using local anesthesia under monitored anesthesia care (MAC). METHODS: A retrospective chart review was performed for patients undergoing parotidectomy under local anesthesia at an academic head and neck surgery center. RESULTS: Six patients deemed high risk for general anesthesia (GA) due to medical comorbidities or with a strong preference to avoid GA underwent parotidectomy using local anesthesia and MAC. Parotidectomy was performed for several indications, including benign tumors, malignant tumors, and chronic sialadenitis. Mean age of patients was 78.0 ±â€¯7.9 years, and all had an American Society of Anesthesia score ≥ 2 and Charlson comorbidity index ≥4. Mean operative time was 102.8 ±â€¯38.3 min, comparable to that of parotidectomy under general anesthesia. No major complications occurred. Minor complications included three cases of temporary postoperative facial nerve weakness limited to 1-2 lower division branches. At most recent follow up (10 to 48 months), all patients were medically stable and disease free. CONCLUSION: In carefully selected patients, parotidectomy under local anesthesia is a viable treatment alternative that can be offered to patients. Successful outcomes require preoperative counseling, meticulous technique, and close collaboration with anesthesia colleagues.

Symptom Distress in Patients With Hepatocellular Carcinoma Toward the End of Life.

PURPOSE/OBJECTIVES: To describe the presence, frequency, severity, and distress of symptoms in outpatients with advanced hepatocellular carcinoma toward the end of life, and the variability in psychological and physical symptom distress between and within patients over time. 
. DESIGN: A prospective, longitudinal, descriptive design. 
. SETTING: Outpatient clinics at two healthcare institutions. 
. SAMPLE: 18 patients (15 men and 3 women) with hepatocellular carcinoma and a mean age of 63.3 years (range = 54-81 years).
. METHODS: Data were collected monthly for six months. Patients completed the Memorial Symptom Assessment Scale, which reports a total score, and three subscales that provide global distress, psychological distress, and physical distress scores.
. MAIN RESEARCH VARIABLES: Global, psychological, and physical distress.
. FINDINGS: Patients reported lack of energy and pain as the most frequent and distressing symptoms. Problems with sexual interest or activity was the fourth most present symptom after drowsiness. Global Distress Index mean scores had notable variability between and within patients over time. During data collection, six patients died. None were referred to palliative care.
. CONCLUSIONS: Gaining knowledge about symptom distress and prevalent symptoms experienced by patients with advanced hepatocellular carcinoma is critical for designing symptom management strategies that are comprehensive and tailored to patients to optimize their quality of life as they approach death.
. IMPLICATIONS FOR NURSING: Nurses play a vital role in advocating for, initiating, and providing comprehensive holistic care based on individual patient needs by facilitating discussions about apparent and less apparent distressing symptoms, including those related to sexuality.

Increased intermediate M1-M2 macrophage polarization and improved cognition in mild cognitive impairment patients on ω-3 supplementation.

Monocyte/macrophages of patients with mild cognitive impairment (MCI) and Alzheimer disease (AD) are defective in phagocytosis and degradation amyloid ß1-42 (Aß1-42), but are improved by ω-3 fatty acids (ω-3s). The hypothesis of this study was that active Aß1-42 phagocytosis by macrophages prevents brain amyloidosis and thus maintains cognition. We studied the effects of self-supplementation with a drink with ω-3s, antioxidants, and resveratrol on Mini-Mental State Examination (MMSE) scores, macrophage M1M2 phenotype [the ratio of inflammatory cluster of differentiation (CD)54+CD80 and proresolution markers CD163+CD206], and Aß1-42 phagocytosis in patients initially diagnosed as having MCI or subjective cognitive impairment (SCI). At baseline, the median MMSE score in patients in both the apolipoprotein E (ApoE) ε3/ε3 and ApoE ε3/ε4 groups was 26.0 and macrophage Aß1-42 phagocytosis was defective. The MMSE rate of change increased in the ApoE ε3/ε3 group a median 2.2 points per year (P = 0.015 compared to 0) but did not change in the ApoE ε3/ε4 group (P = 0.014 between groups). In the ApoE ε3/ε3 group, all patients remained cognitively stable or improved; in the ApoE ε3/ε4 group, 1 recovered from dementia, but 3 lapsed into dementia. The macrophage phenotype polarized in patients bearing ApoE ε3/ε3 to an intermediate (green zone) M1-M2 type at the rate of 0.226 U/yr, whereas in patients bearing ApoE ε3/ε4, polarization was negative (P = 0.08 between groups). The baseline M1M2 type in the extreme M1 (red zone) or M2 (white zone) was unfavorable for cognitive outcome. Aß1-42 phagocytosis increased in both ApoE groups (P = 0.03 in each groups). In vitro, the lipidic mediator resolvin D1 (RvD1) down regulated the M1 type in patients with ApoE ε3/ε3 but in some patients with ε3/ε4, paradoxically up-regulated the M1 type. Antioxidant/ω-3/resveratrol supplementation was associated with favorable immune and cognitive responses in ApoE ε3/ε3 and individual patients bearing ApoE ε3/ε4, and brings into personalized clinical practice the immune benefits expected from ω-3 mediators called resolvins. The validity of this study is limited by its small size and uncontrolled design.-Famenini, S., Rigali, E. A., Olivera-Perez, H. M., Dang, J., Chang, M T., Halder, R., Rao, R. V., Pellegrini, M., Porter, V., Bredesen, D., Fiala, M. Increased intermediate M1-M2 macrophage polarization and improved cognition in mild cognitive impairment patients on ω-3 supplementation.

A Phase 2 Study of Concurrent Radiation Therapy, Temozolomide, and the Histone Deacetylase Inhibitor Valproic Acid for Patients With Glioblastoma.

PURPOSE: Valproic acid (VPA) is an antiepileptic agent with histone deacetylase inhibitor (HDACi) activity shown to sensitize glioblastoma (GBM) cells to radiation in preclinical models. We evaluated the addition of VPA to standard radiation therapy (RT) plus temozolomide (TMZ) in patients with newly diagnosed GBM. METHODS AND MATERIALS: Thirty-seven patients with newly diagnosed GBM were enrolled between July 2006 and April 2013. Patients received VPA, 25 mg/kg orally, divided into 2 daily doses concurrent with RT and TMZ. The first dose of VPA was given 1 week before the first day of RT at 10 to 15 mg/kg/day and subsequently increased up to 25 mg/kg/day over the week prior to radiation. VPA- and TMZ-related acute toxicities were evaluated using Common Toxicity Criteria version 3.0 (National Cancer Institute Cancer Therapy Evaluation Program) and Cancer Radiation Morbidity Scoring Scheme for toxicity and adverse event reporting (Radiation Therapy Oncology Group/European Organization for Research and Treatment). RESULTS: A total of 81% of patients took VPA according to protocol. Median overall survival (OS) was 29.6 months (range: 21-63.8 months), and median progression-free survival (PFS) was 10.5 months (range: 6.8-51.2 months). OS at 6, 12, and 24 months was 97%, 86%, and 56%, respectively. PFS at 6, 12, and 24 months was 70%, 43%, and 38% respectively. The most common grade 3/4 toxicities of VPA in conjunction with RT/TMZ therapy were blood and bone marrow toxicity (32%), neurological toxicity (11%), and metabolic and laboratory toxicity (8%). Younger age and class V recursive partitioning analysis (RPA) results were significant for both OS and PFS. VPA levels were not correlated with grade 3 or 4 toxicity levels. CONCLUSIONS: Addition of VPA to concurrent RT/TMZ in patients with newly diagnosed GBM was well tolerated. Additionally, VPA may result in improved outcomes compared to historical data and merits further study.

Procedural and clinical outcomes after catheter ablation of unstable ventricular tachycardia supported by a percutaneous left ventricular assist device.

BACKGROUND: Hemodynamic support using percutaneous left ventricular assist devices (pLVADs) during catheter mapping and ablation of unstable ventricular tachycardia (VT) can provide effective end-organ perfusion. However, its effect on procedural and clinical outcomes remains unclear. OBJECTIVE: To retrospectively evaluate the procedural and clinical outcomes after the catheter ablation of unstable VT with and without pLVAD support. METHODS: Sixty-eight consecutive unstable, scar-mediated endocardial and/or epicardial VT ablation procedures performed in 63 patients were evaluated. During VT mapping and ablation, hemodynamic support was provided by intravenous inotropes with a pLVAD (n = 34) or without a pLVAD (control; n = 34). RESULTS: Baseline patient characteristics were similar. VT was sustained longer with a pLVAD (27.4 ± 18.7 minutes) than without a pLVAD (5.3 ± 3.6 minutes) (P < .001). A higher number of VTs were terminated during ablation with a pLVAD (1.2 ± 0.9 per procedure) than without a pLVAD (0.4 ± 0.6 per procedure) (P < .001). Total radiofrequency ablation time was shorter with a pLVAD (53 ± 30 minutes) than without a pLVAD (68 ± 33 minutes) (P = .022), but with similar procedural success rates (71% for both pLVAD and control groups; P = 1.000). Although during 19 ± 12 months of follow-up VT recurrence did not differ between pLVAD (26%) and control (41%) groups (P = .305), the composite end point of 30-day rehospitalization, redo-VT ablation, recurrent implantable cardioverter-defibrillator therapies, and 3-month mortality was lower with a pLVAD (12%) than without a pLVAD (35%) (P = .043). CONCLUSION: In this nonrandomized retrospective study, catheter ablation of unstable VT supported by a pLVAD was associated with shorter ablation times and reduced hospital length of stay. While pLVAD support did not affect VT recurrence, it was associated with a lower composite end point of 30-day rehospitalization, redo-VT ablation, recurrent implantable cardioverter-defibrillator therapies, and 3-month mortality.

Management of the open abdomen: from initial operation to definitive closure.

The open abdomen is a relatively new and increasingly common strategy for the management of abdominal emergencies in both trauma and general surgery. The use of an abbreviated laparotomy can reduce mortality associated with conditions such as abdominal compartment syndrome; however, the resulting open abdomen is a complex clinical problem. Modern techniques and technologies are now available that allow for improved management of the open abdomen and the progressive reduction of the fascial defect. Indeed, recent evidence indicates that a large proportion of patients treated with open abdomen can now be closed within the initial hospitalization. These techniques and technologies include the appropriate use of negative pressure therapy and synthetic or biologic repair materials. It is essential that general and trauma surgeons understand the core principles underlying the need for and management of the open abdomen. Toward this goal, an Open Abdomen Advisory Panel was established to identify core principles in the management of the open abdomen and to develop a set of recommendations based on the best available evidence. This review presents the principles and recommendations identified by the Open Abdomen Advisory Panel and provides brief case studies for the illustration of these concepts.

Acute Myocardial Infarction with Hyperoxemic Therapy (AMIHOT): a prospective, randomized trial of intracoronary hyperoxemic reperfusion after percutaneous coronary intervention.

OBJECTIVES: This study sought to determine whether hyperoxemic reperfusion with aqueous oxygen (AO) improves recovery of ventricular function after percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI). BACKGROUND: Hyperbaric oxygen reduces myocardial injury and improves ventricular function when administered during ischemia-reperfusion. METHODS: In a prospective, multicenter study, 269 patients with acute anterior or large inferior AMI undergoing primary or rescue PCI (<24 h from symptom onset) were randomly assigned after successful PCI to receive hyperoxemic reperfusion (treatment group) or normoxemic blood autoreperfusion (control group). Hyperoxemic reperfusion was performed for 90 min using intracoronary AO. The primary end points were final infarct size at 14 days, ST-segment resolution, and delta regional wall motion score index of the infarct zone at 3 months. RESULTS: At 30 days, the incidence of major adverse cardiac events was similar between the control and AO groups (5.2% vs. 6.7%, p = 0.62). There was no significant difference in the incidence of the primary end points between the study groups. In post-hoc analysis, anterior AMI patients reperfused <6 h who were treated with AO had a greater improvement in regional wall motion (delta wall motion score index = 0.54 in control group vs. 0.75 in AO group, p = 0.03), smaller infarct size (23% of left ventricle in control group vs. 9% of left ventricle in AO group, p = 0.04), and improved ST-segment resolution compared with normoxemic controls. CONCLUSIONS: Intracoronary hyperoxemic reperfusion was safe and well tolerated after PCI for AMI, but did not improve regional wall motion, ST-segment resolution, or final infarct size. A possible treatment effect was observed in anterior AMI patients reperfused <6 h of symptom onset.

Innovative therapies: intraoperative intracavitary chemotherapy.

Both phase I studies demonstrated that high-dose cisplatin can be delivered safely with acceptable complication rates. The maximum tolerated doses of 225 mg/m2 and 250 mg/m2 cisplatin, respectively, are higher than any other published report of intrapleural cisplatin. The intrapleural cisplatin doses reported in other trials have been 80 mg/m2, 100 mg/m2, and 200 mg/m2. Despite the use of high-dose intraoperative chemotherapy, the group of 50 patients who underwent EPP experienced mortality and morbidity comparable to the contemporaneous group of 41 patients who did not participate in the protocol, except for increased rates of deep venous thrombosis and diaphragmatic patch failure. The 44 patients who underwent P/D experienced a slightly higher mortality rate and creatinine toxicity rate than the first phase I trial. Given the demographics of this patient cohort (higher age, lower FEV1, and inability to withstand pneumonectomy because of limited cardiopulmonary reserve), however, the mortality and morbidity rates seem acceptable. The pharmacologic data from both studies support our hypothesis that high regional doses of cisplatin can be delivered with less systemic absorption than can be achieved with intravenous administration (data not shown). With the maximum tolerated dose of intracavitary cisplatin and safety of intraoperative administration after surgical resection firmly established by these phase I trials, we are prepared to implement phase II and III studies of EPP and P/D with intraoperative cisplatin lavage. We aim to monitor tumor recurrence and patient survival prospectively and compare these results with historic controls. We also intend to document prospectively the morbidity and mortality of the treatment protocols. Finally, we plan to evaluate the pharmacokinetics of cisplatin by measuring tissue and perfusate levels of active and inactive cisplatin. By approaching the problem of local recurrence after resection of MPM in a careful and methodical manner, we hope to decrease or delay the rate of recurrence and potentially improve longterm survival in patients with this lethal disease.

New lanostanoids from the mushroom Ganoderma lucidum.

From a lipophilic extract of the fruiting body of Ganoderma lucidum, three new lanostanoids, 8beta,9alpha-dihydroganoderic acid J (1), methyl 8beta,9alpha-dihydroganoderate J (2), and 20-hydroxylganoderic acid G (3), along with 12 known lanostanoids and two ergostane sterols were isolated. The structures of 1-3 were determined by interpretation of their spectroscopic data.