Characterisation of aluminium release by the enFlow® fluid-warming system in crystalloids and blood products.

The use of uncoated aluminium-heated plates in an intravenous fluid-warming system has been shown to produce high levels of aluminium in Sterofundin 1/1E, a balanced crystalloid solution. However, the effect of this fluid-warming device on other balanced crystalloid solutions and blood products has not been studied. Using mass spectrometry we measured aluminium levels in Plasma-Lyte 148, compound sodium lactate solution, 4% human albumin solution, expired resuspended packed red cells and fresh frozen plasma that were pumped through an enFlow® fluid-warming system at 2 ml.min-1 . Samples were taken at baseline before heating and then at 10-min intervals up to 60 min with the system set to warm the fluids to 40 °C. High concentrations of aluminium were found for Plasma-Lyte 148 and compound sodium lactate solutions (mean (SD) 223 (0.6) µmol.l-1 and 163 (0.2) µmol.l-1 at 60 min, respectively); both concentrations were significantly greater than the United States Food and Drug Administration recommended maximum limit for aluminium in intravenous nutrition of 25 µg.l-1 (0.9 µmol.l-1 ). Lower aluminium levels were found in 4% human albumin solutions, expired resuspended red cells and fresh frozen plasma at 60 min (mean (SD) 5.7 (0.1) µmol.l-1 , 2.7 (0.0) µmol.l-1 and 2.3 (0.4) µmol.l-1 , respectively). The process allowing addition of aluminium to be added to Sterofundin 1/1E by the enFlow fluid warmer also occurs in Plasma-Lyte 148 and compound sodium lactate solutions and to a lesser degree in blood products. The exact mechanism facilitating this process and its clinical significance remain unclear.

Pharmacological and electrophysiological characterization of AZSMO-23, an activator of the hERG K(+) channel.

BACKGROUND AND PURPOSE: We aimed to characterize the pharmacology and electrophysiology of N-[3-(1H-benzimidazol-2-yl)-4-chloro-phenyl]pyridine-3-carboxamide (AZSMO-23), an activator of the human ether-a-go-go-related gene (hERG)-encoded K(+) channel (Kv 11.1). EXPERIMENTAL APPROACH: Automated electrophysiology was used to study the pharmacology of AZSMO-23 on wild-type (WT), Y652A, F656T or G628C/S631C hERG, and on other cardiac ion channels. Its mechanism of action was characterized with conventional electrophysiology. KEY RESULTS: AZSMO-23 activated WT hERG pre-pulse and tail current with EC50 values of 28.6 and 11.2 µM respectively. At 100 µM, pre-pulse current at +40 mV was increased by 952 ± 41% and tail current at -30 mV by 238 ± 13% compared with vehicle values. The primary mechanism for this effect was a 74.5 mV depolarizing shift in the voltage dependence of inactivation, without any shift in the voltage dependence of activation. Structure-activity relationships for this effect were remarkably subtle, with close analogues of AZSMO-23 acting as hERG inhibitors. AZSMO-23 blocked the mutant channel, hERG Y652A, but against another mutant channel, hERG F656T, its activator activity was enhanced. It inhibited activity of the G628C/S631C non-inactivating hERG mutant channel. AZSMO-23 was not hERG selective, as it blocked hKv 4.3-hKChIP2.2, hCav 3.2 and hKv 1.5 and activated hCav 1.2/ß2/α2δ channels. CONCLUSION AND IMPLICATIONS: The activity of AZSMO-23 and those of its close analogues suggest these compounds may be of value to elucidate the mechanism of type 2 hERG activators to better understand the pharmacology of this area from both a safety perspective and in relation to treatment of congenital long QT syndrome.

Association between preoperative glucocorticoids and long-term survival and cancer recurrence after colectomy: follow-up analysis of a previous randomized controlled trial.

BACKGROUND: The effect of anaesthetic drugs on long-term oncological outcomes after cancer surgery is an area of current interest. Dexamethasone is widely used in anaesthetic practice; however, its effect on long-term survival and cancer outcomes is not known. This study presents the results of a 5-yr follow-up of patients receiving dexamethasone before elective colectomy as part of a previous randomized clinical trial. METHODS: Sixty patients who underwent elective open colonic resection for any indication between June 2006 and March 2008 were randomized to receive either 8 mg i.v. dexamethasone or placebo before surgery. A 5-yr follow-up analysis was conducted to evaluate overall survival, disease-free survival and recurrence specifically for patients undergoing resection for Stage I-III colon cancer. Kaplan-Meier analysis was performed and log-rank test was used to evaluate difference in survival between groups. RESULTS: Forty-three of the 60 subjects had Stage I-III colon cancer and were included in the follow-up analysis. Twenty received preoperative dexamethasone and 23 received placebo. There were no significant differences between groups in baseline or disease characteristics. No differences were found between groups for overall or disease-free survival. In the dexamethasone group, there was a significantly higher rate of distant recurrence (6 compared with 1, P=0.04). CONCLUSIONS: Preoperative dexamethasone was associated with a higher rate of distant recurrence in patients undergoing colectomy for colon cancer. Given the small sample size, this finding should be interpreted with caution, but warrants further investigation in a prospective study.

Systematic review and meta-analysis of oesophageal Doppler-guided fluid management in colorectal surgery.

BACKGROUND: Oesophageal Doppler monitor (ODM)-guided fluid therapy has been recommended for routine use in patients undergoing colorectal surgery. However, recent trials have suggested either equivalent or inferior results for patients randomized to ODM-guided fluid management, especially when compared with fluid restriction or within the context of optimized perioperative care. Hence, an updated systematic review and meta-analysis was conducted. METHODS: A systematic review and meta-analysis was conducted of all randomized trials exploring ODM-guided fluid management in major colorectal surgery with the endpoints total complications and length of hospital stay (LOS). Subset analyses were planned a priori specifically to investigate the role of the ODM in the context of fluid restriction or optimized perioperative care. RESULTS: Six high-quality trials comprising a total of 691 patients were included in the final analysis. ODM-guided fluid therapy did not influence the incidence of complications (odds ratio 0·74, 95 per cent confidence interval (c.i.) 0·50 to 1·11; P = 0·15), with moderate heterogeneity in the results (I(2) = 33 per cent; P = 0·19). There was no difference in mean LOS between patients receiving ODM-guided fluid therapy and controls: mean difference -0·88 (95 per cent c.i. -2·89 to 1·13) days (P = 0·39). There was no difference in complications or LOS when ODM-guided fluid therapy was compared with fluid restriction or used within an otherwise optimized perioperative environment. CONCLUSION: ODM-guided fluid therapy did not influence LOS or complications in patients undergoing colorectal surgery. Results favouring the ODM were seen only in early studies, whereas newer trials did not show any benefit from such monitoring.

Randomized clinical trial of goal-directed fluid therapy within an enhanced recovery protocol for elective colectomy.

BACKGROUND: Goal-directed fluid therapy (GDFT) has been compared with liberal fluid administration in non-optimized perioperative settings. It is not known whether GDFT is of value within an enhanced recovery protocol incorporating fluid restriction. This study evaluated GDFT under these circumstances in patients undergoing elective colectomy. METHODS: Patients undergoing elective laparoscopic or open colectomy within an established enhanced recovery protocol (including fluid restriction) were randomized to GDFT or no GDFT. Bowel preparation was permitted for left colonic operations at the surgeon's discretion. Exclusion criteria included rectal tumours and stoma formation. The primary outcome was a patient-reported surgical recovery score (SRS). Secondary endpoints included clinical outcomes and physiological measures of recovery. RESULTS: Eighty-five patients were randomized, and there were 37 patients in each group for analysis. Nine patients in the GDFT and four in the fluid restriction group received oral bowel preparation for either anterior resection (12) or subtotal colectomy (1). Patients in the GDFT group received more colloid during surgery (mean 591 versus 297 ml; P = 0·012) and had superior cardiac indices (mean corrected flow time 374 versus 355 ms; P = 0·018). However, no differences were observed between the GDFT and fluid restriction groups with regard to surgical recovery (mean SRS after 7 days 47 versus 46 respectively; P = 0·853), other secondary outcomes (mean aldosterone/renin ratio 9 versus 8; P = 0·898), total postoperative fluid (median 3750 versus 2400 ml; P = 0·604), length of hospital stay (median 6 versus 5 days; P = 0·570) or number of patients with complications (26 versus 27; P = 1·000). CONCLUSION: GDFT did not provide clinical benefit in patients undergoing elective colectomy within a protocol incorporating fluid restriction. REGISTRATION NUMBER: NCT00911391 (http://www.clinicaltrials.gov).

Oesophageal Doppler-guided fluid administration in colorectal surgery: critical appraisal of published clinical trials.

The evidence underpinning oesophageal Doppler monitoring (ODM)-guided fluid administration in colorectal surgery has not been critically appraised despite quantitative meta-analyses. A qualitative systematic review of the methodology and findings of all published randomised-controlled trials (RCTs) exploring ODM-guided fluid administration in major abdominal surgery was conducted. Four, well-designed single-centre trials inclusive of 393 patients in total have primarily demonstrated that ODM-guided intraoperative fluid administration decreases hospital length of stay (LOS) and complications by optimising intraoperative cardiac parameters. One subsequently published RCT shows that ODM-guided fluid administration predisposes to a greater LOS and significantly increased complications. However, all the trials have been hampered by imprecise definitions with heterogeneity in patient selection, intraoperative fluid administration strategies and methods of outcome assessment. ODM-guided fluid administration has only been investigated in the setting of laparoscopic colonic surgery and within an optimised perioperative care protocol in one trial, where it was not shown to be beneficial. Nevertheless, it was recommended for use in this context before the trial was even published. ODM-guided fluid administration has not been compared with intraoperative fluid restriction. Current evidence regarding the use of Doppler-guided fluid administration is limited by heterogeneity in the trial design, and the initial clinical benefits observed may be largely offset by recent advances in surgical techniques and perioperative care.

An introduction to QT interval prolongation and non-clinical approaches to assessing and reducing risk.

Owing to its association with Torsades de Pointes, drug-induced QT interval prolongation has been and remains a significant hurdle to the development of safe, effective medicines. Genetic and pharmacological evidence highlighting the pivotal role the human ether-a-go-go-related gene (hERG) channel was a critical step in understanding how to start addressing this issue. It led to the development of hERG assays with the rapid throughput needed for the short timescales required in early drug discovery. The resulting volume of hERG data has fostered in silico models to help chemists design compounds with reduced hERG potency. In early drug discovery, a pragmatic approach based on exceeding a given potency value has been required to decide when a compound is likely to carry a low QT risk, to support its progression to late-stage discovery. At this point, the in vivo efficacy and metabolism characteristics of the potential drug are generally defined, as well its safety profile, which includes usually a dog study to assess QT interval prolongation risk. The hERG and in vivo QT data, combined with the likely indication and the estimated free drug level for efficacy, are put together to assess the risk that the potential drug will prolong QT in man. Further data may be required to refine the risk assessment before making the major investment decisions for full development. The non-clinical data are essential to inform decisions about compound progression and to optimize the design of clinical QT studies.

A rabbit Langendorff heart proarrhythmia model: predictive value for clinical identification of Torsades de Pointes.

BACKGROUND AND PURPOSE: The rabbit isolated Langendorff heart model (SCREENIT) was used to investigate the proarrhythmic potential of a range of marketed drugs or drugs intended for market. These data were used to validate the SCREENIT model against clinical outcomes. EXPERIMENTAL APPROACH: Fifty-five drugs, 3 replicates and 2 controls were tested in a blinded manner. Proarrhythmia variables included a 10% change in MAPD(60), triangulation, instability and reverse frequency-dependence of the MAP. Early after-depolarisations, ventricular tachycardia, TdP and ventricular fibrillation were noted. Data are reported at nominal concentrations relative to EFTPC(max). Proarrhythmic scores were assigned to each drug and each drug category. KEY RESULTS: Category 1 and 2 drugs have the highest number of proarrhythmia variables and overt proarrhythmia while Category 5 drugs have the lowest, at every margin. At 30-fold the EFTPC(max), the mean proarrhythmic scores are: Category 1, 101+/-24; Category 2, 101+/-14; Category 3, 72+/-20; Category 4, 59+/-16 and Category 5, 22+/-9 points. Only drugs in Category 5 have mean proarrhythmic scores, below 30-fold, that remain within the Safety Zone. CONCLUSIONS AND IMPLICATIONS: A 30-fold margin between effects and EFTPC(max) is sufficiently stringent to provide confidence to proceed with a new chemical entity, without incurring the risk of eliminating potentially beneficial drugs. The model is particularly useful where compounds have small margins between the hERG IC(50) and predicted EFTPC(max). These data suggest this is a robust and reliable assay that can add value to an integrated QT/TdP risk assessment.

Optimisation and validation of a medium-throughput electrophysiology-based hERG assay using IonWorks HT.

INTRODUCTION: Regulatory and competitive pressure to reduce the QT interval prolongation risk of potential new drugs has led to focus on methods to test for inhibition of the human ether-a-go-go-related gene (hERG)-encoded K+ channel, the primary molecular target underlying this safety issue. Here we describe the validation of a method that combines medium-throughput with direct assessment of channel function. METHODS: The electrophysiological and pharmacological properties of hERG were compared using two methods: conventional, low-throughput electrophysiology and planar-array-based, medium-throughput electrophysiology (IonWorks HT). A pharmacological comparison was also made between IonWorks HT and an indirect assay (Rb+ efflux). RESULTS: Basic electrophysiological properties of hERG were similar whether recorded conventionally (HEK cells) or using IonWorks HT (CHO cells): for example, tail current V1/2 -12.1+/-5.0 mV (32) for conventional and -9.5+/-6.0 mV (46) for IonWorks HT (mean+/-S.D. (n)). A key finding was that as the number of cells per well was increased in IonWorks HT, the potency reported for a given compound decreased. Using the lowest possible cell concentration (250,000 cells/ml) and 89 compounds spanning a broad potency range, the pIC50 values from IonWorks HT (CHO-hERG) were found to correlate well with those obtained using conventional methodology (HEK-hERG)(r=0.90; p<0.001). Further validation using CHO-hERG cells with both methods confirmed the correlation (r=0.94; p<0.001). In contrast, a comparison of IonWorks HT and Rb+ efflux data with 649 compounds using CHO-hERG cells showed that the indirect assay consistently reported compounds as being, on average, 6-fold less potent, though the differences varied depending on chemical series. DISCUSSION: The main finding of this work is that providing a relatively low cell concentration is used in IonWorks HT, the potency information generated correlates well with that determined using conventional electrophysiology. The effect on potency of increasing cell concentration may relate to a reduced free concentration of test compound owing to partitioning into cell membranes. In summary, the IonWorks HT hERG assay can generate pIC50 values based on a direct assessment of channel function in a timeframe short enough to influence chemical design.

Weakfish sonic muscle: influence of size, temperature and season.

The influence of temperature, size and season on the sounds produced by the sonic muscles of the weakfish Cynoscion regalis are categorized and used to formulate a hypothesis about the mechanism of sound generation by the sonic muscle and swimbladder. Sounds produced by male weakfish occur at the time and location of spawning and have been observed in courtship in captivity. Each call includes a series of 6-10 sound pulses, and each pulse expresses a damped, 2-3 cycle acoustic waveform generated by single simultaneous twitches of the bilateral sonic muscles. The sonic muscles triple in mass during the spawning season, and this hypertrophy is initiated by rising testosterone levels that trigger increases in myofibrillar and sarcoplasmic cross-sectional area of sonic muscle fibers. In response to increasing temperature, sound pressure level (SPL), dominant frequency and repetition rate increase, and pulse duration decreases. Likewise, SPL and pulse duration increase and dominant frequency decreases with fish size. Changes in acoustic parameters with fish size suggest the possibility that drumming sounds act as an 'honest' signal of male fitness during courtship. These parameters also correlate with seasonally increasing sonic muscle mass. We hypothesize that sonic muscle twitch duration rather than the resonant frequency of the swimbladder determines dominant frequency. The brief (3.5 ms), rapidly decaying acoustic pulses reflect a low-Q, broadly tuned resonator, suggesting that dominant frequency is determined by the forced response of the swimbladder to sonic muscle contractions. The changing dominant frequency with temperature in fish of the same size further suggests that frequency is not determined by the natural frequency of the bladder because temperature is unlikely to affect resonance. Finally, dominant frequency correlates with pulse duration (reflecting muscle twitch duration), and the inverse of the period of the second cycle of acoustic energy approximates the recorded frequency. This paper demonstrates for the first time that the dominant frequency of a fish sound produced by a single muscle twitch is apparently determined by the velocity of the muscle twitch rather than the natural frequency of the swimbladder.

Preventive medicine 2000: changing contexts and opportunities.

The teaching of preventive medicine in the medical school curriculum occurs both in independent and in interdisciplinary courses and units. A survey was conducted to examine the changes in preventive medicine context, content, and allotted hours that have occurred in the transition from the traditional Flexnerian curriculum to the more interdisciplinary, centrally controlled curriculum. Data on medical school curricula for 1990-91, 1993-94, 1995-96, and 1998-99 were examined for the 126 U.S. and 16 Canadian medical schools. By 1998-99, 35 schools moving to the new interdisciplinary format had retained preventive medicine teaching as a separate course, although the courses usually had incorporated topics that went beyond the traditional ones. In another 35 schools, preventive medicine hours had been lost in the transition; but in 25 of these new courses it was clear that preventive medicine played a very significant role. It can be assumed that the lost hours were more than replaced as preventive medicine concepts permeated these courses. Of greatest importance were the hallmark courses of the six nontraditional curricula that had designated preventive medicine a major-theme course. However, at ten schools, preventive medicine listings disappeared in the move to nontraditional curricula. Preventive medicine educators must step forward to use curricular restructuring to expand the role of preventive medicine in the curricula of their institutions, whether in stand-alone or in interdisciplinary courses. The goal, as always, is to provide future physicians with the knowledge and skills they need to provide proper care to their patients.

Effects of fish size and temperature on weakfish disturbance calls: implications for the mechanism of sound generation.

To categorize variation in disturbance calls of the weakfish Cynoscion regalis and to understand their generation, we recorded sounds produced by different-sized fish, and by similar-sized fish at different temperatures, as well as muscle electromyograms. Single, simultaneous twitches of the bilateral sonic muscles produce a single sound pulse consisting of a two- to three-cycle acoustic waveform. Typical disturbance calls at 18 degrees C consist of trains of 2-15 pulses with a sound pressure level (SPL) of 74 dB re 20 microPa at 10 cm, a peak frequency of 540 Hz, a repetition rate of 20 Hz and a pulse duration of 3.5 ms. The pulse duration suggests an incredibly short twitch time. Sound pressure level (SPL) and pulse duration increase and dominant frequency decreases in larger fish, whereas SPL, repetition rate and dominant frequency increase and pulse duration decreases with increasing temperature. The dominant frequency is inversely related to pulse duration and appears to be determined by the duration of muscle contraction. We suggest that the lower dominant frequency of larger fish is caused by a longer pulse (=longer muscle twitch) and not by the lower resonant frequency of a larger swimbladder.

The effects of seasonal hypertrophy and atrophy on fiber morphology, metabolic substrate concentration and sound characteristics of the weakfish sonic muscle.

Male weakfish Cynoscion regalis possess highly specialized, bilateral, striated sonic muscles used in sound production associated with courtship. Androgen-driven hypertrophy of the muscles during the late spring spawning period results in a tripling of sonic muscle mass followed by post-spawning atrophy. This study examined the morphological and biochemical changes underlying seasonal changes in sonic muscle mass and the functional effects of these on contraction as measured by sound production. Sonic muscle fiber cross-sectional area (CSA) increased significantly during the period of hypertrophy and then decreased by nearly 60%. Both the CSA of the contractile cylinder and that of the peripheral sarcoplasm decreased significantly by late summer, with the peripheral ring of sarcoplasm virtually disappearing. Muscle protein content followed a similar trend, suggesting a major loss of structural elements during atrophy. Muscle glycogen and lipid content decreased precipitously in early June during the period of maximal sound production. Sound pressure level increased and sound pulse duration decreased with increasing sonic muscle mass, indicating that sonic muscle fibers contract with greater force and shorter duration during the spawning season. Neither the pulse repetition rate nor the number of pulses varied seasonally or with muscle mass, suggesting that the effects of steroids on the acoustic variables are more pronounced peripherally than in the central nervous system. Seasonal sonic muscle hypertrophy, therefore, functions as a secondary sexual characteristic that maximizes vocalization amplitude during the spawning period.

Prophylactic chemoradiation of inguinofemoral lymph nodes in patients with locally extensive vulvar cancer.

OBJECTIVE: Primary surgical resection of locally advanced squamous cancer of the vulva may compromise the integrity of important midline structures such as the anus, clitoris, urethra, and vagina. Chemoradiation (synchronous radiation and cytotoxic chemotherapy) has been used as alternative initial treatment which may serve as definitive management for some patients, or may reduce the scope and functional sequelae of subsequent surgery in others. Inguinofemoral node dissection is associated with substantial risk of both acute and late morbidity, prompting consideration of elective inclusion of groin nodes within the irradiated volume and deletion of subsequent groin surgery. Concern that disease relapse in the groins is potentially fatal suggested the prudence of formal outcome assessment of our recent experience with prophylactic treatment of clinically uninvolved groin nodes in the context of concurrent chemoradiation for locally advanced primary vulvar cancer. METHODS: A review was conducted of 23 previously untreated patients with locally advanced squamous cancer of the vulva (2 T2, 20 T3, 1 T4) and clinically uninvolved groin nodes (1969 FIGO stages 14 N0, 4 N1, and 5 N2 with negative node biopsies) who were treated since 1987 with chemoradiation administered to a volume electively including bilateral inguinofemoral nodes. These patients did not undergo subsequent groin surgery. RESULTS: With follow-up from 6 to 98 months (mean, 45.3 months; median, 42 months), no patient has failed in the prophylactically irradiated inguinofemoral nodes. No patient has developed lymphedema, vascular insufficiency, or neurological injury in a lower extremity, and no patient has experienced aseptic necrosis of a femur. CONCLUSIONS: Elective irradiation of the groin nodes in the context of initial chemoradiation for locally advanced vulvar cancer is an effective therapy associated with acceptable acute toxicity and minimal late sequelae. It constitutes a sensible alternative to groin dissection in this patient population.

Effects of exogenous testosterone on sonic muscle mass in the weakfish, Cynoscion regalis.

Three testosterone (T) implant experiments were carried out to investigate the hormonal control of seasonal hypertrophy in the sound producing, or sonic, muscles of the weakfish Cynoscion regalis. The first experiment examined the role of T in the seasonal increase in sonic muscle mass noted in adult male weakfish during the spring and summer spawning period. Specimens held over-winter were implanted with T or vehicle prior to the natural spawning season. The sonic muscle mass of the T-implanted group increased two and a half-fold over a period of 3 weeks, while that of the sham-implanted group did not change. At the end of the experiment, the cross-sectional area of the sonic muscle fibers in the T-implanted group averaged 500 microns 2, while that of the sham-implanted group averaged 300 microns 2. In a second experiment, the elevated sonic muscle mass of spawning male weakfish was sustained with pharmacological levels of plasma T for a period of 4 months following the spawning season. The sonic muscle mass of the sham-implanted group decreased to typical postseason values. In a third experiment, male and female age-0 weakfish were held over-winter and then implanted with T in advance of their first natural spawning season. The sonic muscles of the T-treated male specimens attained twice the mass of those of the sham-implanted male specimens in 3 weeks time. No sonic muscle development was noted in any of the female specimens.

Treatment of childhood acute myeloid leukaemia using the BFM-83 protocol.

Thirty children presenting with acute nonlymphoblastic leukaemia from June 1984 to December 1989 were treated at one UK centre using a West German protocol, AML-BFM-83. This consisted of Induction, an intensive outpatient-based Consolidation regimen with seven different drugs and cranial irradiation, and Continuation therapy with thioguanine and cytosine arabinoside for 2 years with additional Adriamycin in the first year. Twenty-five children achieved complete remission (83%). There were two early deaths from haemorrhage and infection and three from Induction failure. After a median follow-up time of 60 months, nine relapses have occurred, all in the bone marrow. Life table analysis revealed a probability for survival at 5 years of 47%, event-free survival 43%, and event-free interval 50%. Median bed occupancy for chemotherapy and toxicity was 41 days, with median hospital stays of 29 days for Induction, 11 days for Consolidation and less than 1 day for Continuation. This data suggests that long-term remissions can be achieved in just under half of children with acute nonlymphoblastic leukaemia while creating only modest demands on inpatient resources.

Gamma probe location of 111indium-labeled B72.3: an extension of immunoscintigraphy.

Eight colorectal and 5 ovarian cancer patients were evaluated with preoperative immunoscintigraphy and intraoperative gamma probe detection of 111indium-labeled monoclonal antibody B72.3. Immunoscintigraphy detected the presence of tumor in every patient shown to have tumor at surgery. There was one false-positive scan. A total of 21 pathologically verified lesions were identified at surgery in the 11 patients with tumor. Immunoscintigraphy localized 12 (57%) and intraoperative gamma probe detection located 17 (81%) of the lesions. Intraoperative probe detection located 6 of 8 lesions smaller than 1 cm and 3 lesions that were not identified on initial surgical exploration. The gamma probe offers information that is complementary to immunoscintigraphy in that (1) it aids the surgeon in locating intra- and extra-abdominal lesions previously identified by immunoscintigraphy, (2) it locates lesions too small to be seen by immunoscintigraphy alone, (3) it locates lesions that otherwise might be missed at surgery, and (4) it provides objective evidence for adequacy of surgical resection of cancer in the abdominal cavity.

Synchronous radiation and cytotoxic chemotherapy for locally advanced or recurrent squamous cancer of the vulva.

Between July 1987 and September 1991 a program of external beam radiation and synchronous, radiopotentiating chemotherapy was employed to treat 25 women with locoregionally advanced or locoregionally recurrent squamous cancer of the vulva. Of 18 previously untreated patients, 1 was Stage II, 10 were Stage III, 6 were Stage IVA, and 1 was Stage IVB. Reasons for patient referral for nonsurgical management included the presence of initially unresectable disease (5 patients), disease extent which would have necessitated partial or total exenteration if treated surgically (9 patients), disease extent predictive of inadequate surgical margins (less than 1 cm gross margin) if treated by less than exenterative surgery (8 patients), and severe comorbid illness precluding surgical management (3 patients). Complete clinical response was obtained in 16 of 18 previously untreated patients (89%) and in 4 of 7 patients with recurrent disease following vulvar surgery (57%). Of 20 patients achieving a complete clinical response, 3 patients have relapsed within the irradiated volume at 11, 38, and 48 months following completion of treatment. Fourteen patients remain alive and continuously cancer free from 2-52 months after completion of treatment (median follow-up 24 months). This experience suggests that initial management with radiation and chemotherapy may offer some patients with locally advanced squamous cancer of the vulva an alternative to exenterative surgery and may hold curative potential for some patients with surgically unresectable or medically inoperable disease.