Neoadjuvant cetuximab, twice-weekly gemcitabine, and intensity-modulated radiotherapy (IMRT) in patients with pancreatic adenocarcinoma.

BACKGROUND: Neoadjuvant therapy has been investigated for localized and locally advanced pancreatic ductal adenocarcinoma (PDAC) but no standard of care exists. Combination cetuximab/gemcitabine/radiotherapy demonstrates encouraging preclinical activity in PDAC. We investigated cetuximab with twice-weekly gemcitabine and intensity-modulated radiotherapy (IMRT) as neoadjuvant therapy in patients with localized or locally advanced PDAC. EXPERIMENTAL DESIGN: Treatment consisted of cetuximab load at 400 mg/m(2) followed by cetuximab 250 mg/m(2) weekly and gemcitabine 50 mg/m(2) twice-weekly given concurrently with IMRT to 54 Gy. Following therapy, patients were considered for resection. RESULTS: Thirty-seven patients were enrolled with 33 assessable for response. Ten patients (30%) manifested partial response and 20 (61%) manifested stable disease by RECIST. Twenty-five patients (76%) underwent resection, including 18/23 previously borderline and 3/6 previously unresectable tumors. Twenty-three (92%) of these had negative surgical margins. Pathology revealed that 24% of resected tumors had grade III/IV tumor kill, including two pathological complete responses (8%). Median survival was 24.3 months in resected patients. Outcome did not vary by epidermal growth factor receptor status. CONCLUSIONS: Neoadjuvant therapy with cetuximab/gemcitabine/IMRT is tolerable and active in PDAC. Margin-negative resection rates are high and some locally advanced tumors can be downstaged to allow for complete resection with encouraging survival. Pathological complete responses can occur. This combination warrants further investigation.

Phase I study of twice-weekly gemcitabine and concomitant external-beam radiotherapy in patients with adenocarcinoma of the pancreas.

PURPOSE: To determine the maximum tolerated dose and dose-limiting toxicity associated with twice-weekly gemcitabine and concomitant external-beam radiotherapy in patients with adenocarcinoma of the pancreas. METHODS AND MATERIALS: Twenty-one patients with biopsy-proven adenocarcinoma of the pancreas were treated with external-beam radiotherapy to a dose of 50.4 Gy in 28 fractions, concurrent with gemcitabine, infused over 30 min before irradiation on a Monday and Thursday schedule. The dose of gemcitabine was escalated in 5 cohorts of 3--6 patients each. Initial gemcitabine dose was 10 mg/m(2), with dose escalation until dose-limiting toxicity was observed. RESULTS: The maximum tolerated dose of gemcitabine was 50 mg/m(2), when given in a twice-weekly schedule with radiation. Dose-limiting toxicity was seen in 2 patients at 60 mg/m(2), and consisted of severe upper gastrointestinal bleeding approximately 1 month after completion of treatment. Six patients had radiographic evidence of response to treatment, and 5 of these underwent complete surgical resection. Three patients who underwent complete resection had been deemed to have unresectable tumors before enrollment on trial. Four patients are alive, including 2 without evidence of disease more than 1 year after resection. CONCLUSION: The combination of external-beam radiation and twice-weekly gemcitabine at a dose of 50 mg/m(2) is well tolerated and shows promising activity for the treatment of pancreatic cancer. Our data suggest a higher maximum tolerated dose and different dose-limiting toxicity than previously reported. Further investigation of this regimen is warranted.

Interval hepatic resection of colorectal metastases improves patient selection.

HYPOTHESIS: Interval reevaluation for resectability of hepatic colorectal metastases aids patient selection. DESIGN: A retrospective review. SETTING: A tertiary care medical center. PATIENTS AND METHODS: From January 1, 1985, to July 1, 1998, 318 patients with colorectal hepatic metastases were identified. Resectable lesions (N = 73) were divided into synchronous (n = 36) or metachronous (n = 37) and retrospectively reviewed for immediate resection or interval reevaluation. Kaplan-Meier survival curves of treatment groups were compared by the log-rank test. RESULTS: Survival curves of patients with synchronous and metachronous lesions undergoing interval reevaluation vs. immediate resection were not significantly different (P = .74 and P = .65, respectively). No lesions from patients who underwent interval reevaluation became unresectable due to growth of the initial metastases. After interval reevaluation, 8 (29%) of 28 patients with synchronous metastases were spared the morbidity of laparotomy because of distant or an increased number of metastases and 10 (36%) of 28 patients were spared the morbidity of hepatic resection at the time of interval laparotomy. Actuarial median and 5-year survival of patients after delayed hepatic resection (51 months and 45%, respectively) were significantly improved compared with those of all other patients with resectable metastases (23 months and 7%, respectively) (P = .02). For patients with metachronous lesions who underwent interval reevaluation, 4 (29%) of 14 patients were spared the morbidity of laparotomy because of an increased number of hepatic or distant metastases. CONCLUSIONS: Delaying hepatic resection for metastatic colorectal cancer does not impair survival. Potentially, two thirds of patients can avoid maj or hepatic surgery. For synchronous metastases, delaying hepatic resection appears to select patients who will benefit from hepatic resection.

Effects of intraoperative irradiation (IORT) and intraoperative hyperthermia (IOHT) on canine sciatic nerve: histopathological and morphometric studies.

PURPOSE/OBJECTIVE: Peripheral neuropathies have emerged as the major dose-limiting complication reported after intraoperative radiation therapy (IORT). The combination of IORT with hyperthermia may further increase the risk of peripheral nerve injury. The objective of this study was to evaluate histopathological and histomorphometric changes in the sciatic nerve of dogs, after IORT with or without hyperthermia treatment. METHODS AND MATERIALS: Young adult beagle dogs were randomized into five groups of 3-5 dogs each to receive IORT doses of 16, 20, 24, 28, or 32 Gy. Six groups of 4-5 dogs each received IORT doses of 12, 16, 20, 24, or 28 Gy simultaneously with 44 degrees C of intraoperative hyperthermia (IOHT) for 60 min. One group of dogs acted as hyperthermia-alone controls. Two years after the treatment, dogs were euthanized, and histopathological and morphometric analyses were performed. RESULTS: Qualitative histological analysis showed prominent changes such as focal necrosis, mineralization, fibrosis, and severe fiber loss in dogs which received combined treatment. Histomorphometric results showed a significantly higher decrease in axon and myelin and small blood vessels, with a corresponding increase in connective tissue in dogs receiving IORT plus hyperthermia treatment. The effective dose for 50% of nerve fiber loss (ED50) in dogs exposed to IORT only was 25.3 Gy. The ED50 for nerve fiber loss in dogs exposed to IORT combined with IOHT was 14.8 Gy. The thermal enhancement ratio (TER) was 1.7. CONCLUSION: The probability of developing peripheral neuropathies in a large animal model is higher when IORT is combined with IOHT, when compared to IORT application alone. To minimize the risk of peripheral neuropathy, clinical treatment protocols for the combination of IORT and hyperthermia should not assume a thermal enhancement ratio (TER) to be lower than 1.5.

Short-term outcome after mesh or shouldice herniorrhaphy: a randomized, prospective study.

BACKGROUND: Retrospective analyses have shown that long-term recurrence rates after Lichtenstein mesh and Shouldice herniorrhaphies are low. Therefore differences in short-term outcome may be important determinants of one's choice of repair. Although proponents of the mesh repair claim that their methods is less morbid, to our knowledge no prospective comparative studies of short-term morbidity have been reported. METHODS: One hundred five adult patients were randomized to undergo either a mesh or Shouldice inguinal hernia repair. Postoperative pain, narcotic use, and time to resumption of usual activities and employment were recorded. Patients were blinded to the type of repair received until all data were collected. RESULTS: There was no difference between the herniorrhaphy methods with respect to postoperative pain, duration of narcotic use, and time to resumption of usual activity and employment. Recovery was rapid for both groups of patients. By 3 days after operation, 50% of patients rated their pain as very mild or less and no longer required narcotic analgesics. Patients in both groups returned to usual activity and work by a median of 9 days after operation. CONCLUSION: Both of these well-established methods can be used to repair inguinal hernias with local anesthetics in an outpatient setting with minimal morbidity. Despite the "tension-free" design of the mesh repair, short-term outcomes of mesh and Shouldice repairs of inguinal hernias do not differ.

Effects of intraoperative irradiation and intraoperative hyperthermia on canine sciatic nerve: neurologic and electrophysiologic study.

PURPOSE: Late radiation injury to peripheral nerve may be the limiting factor in the clinical application of intraoperative radiation therapy (IORT). The combination of IORT with intraoperative hyperthermia (IOHT) raises specific concerns regarding the effects on certain normal tissues such as peripheral nerve, which might be included in the treatment field. The objective of this study was to compare the effect of IORT alone to the effect of IORT combined with IOHT on peripheral nerve in normal beagle dogs. METHODS AND MATERIALS: Young adult beagle dogs were randomized into five groups of three to five dogs each to receive IORT doses of 16, 20, 24, 28, or 32 Gy to 5 cm of surgically exposed right sciatic nerve using 6 MeV electrons and six groups of four to five dogs each received IORT doses of 0, 12,16, 20, 24, or 28 Gy simultaneously with 44 degrees C of IOHT for 60 min. IOHT was performed using a water circulating hyperthermia device with a multichannel thermometry system on the surgically exposed sciatic nerve. Neurologic and electrophysiologic examinations were done before and monthly after treatment for 24 months. Electrophysiologic studies included electromyographic (EMG) examinations of motor function, as well as motor nerve conduction velocities studies. RESULTS: Two years after treatment, the effective dose for 50% complication (ED50) for limb paresis in dogs exposed to IORT only was 22 Gy. The ED50 for paresis in dogs exposed to IORT combined with IOHT was 15 Gy. The thermal enhancement ratio (TER) was 1.5. Electrophysiologic studies showed more prominent changes such as EMG abnormalities, decrease in conduction velocity and amplitude of the action potential, and complete conduction block in dogs that received the combination of IORT and IOHT. The latency to development of peripheral neuropathies was shorter for dogs exposed to the combined treatment. CONCLUSION: The probability of developing peripheral neuropathies in a large animal model was higher for IORT combined with IOHT, than for IORT alone. The dose required to produce the same level of late radiation injury to the sciatic nerve was reduced by a factor of 1.5 (TER) if IORT was combined with 44 degrees C of IOHT for 60 min.

Morphine inhibits spontaneous and cytokine-enhanced natural killer cell cytotoxicity in volunteers.

BACKGROUND: Opioids are used by patients who have conditions ranging from the acute pain of surgery and chronic cancer pain to substance abuse. Despite their widespread use and considerable experimental data about them, little is known about how opioids may alter in vivo immunity in humans. This study was designed to evaluate the in vivo effect of morphine on human peripheral blood immune functions. METHODS: Healthy volunteers underwent continuous exposure to morphine for 36 h including a 24-h intravenous infusion in the hospital. Peripheral blood was drawn for immune function studies at five measurement times before, during, and after morphine exposure. Peripheral blood mononuclear cells were tested for acute and gamma-interferon-stimulated natural killer cell cytotoxicity (NKCC), antibody-dependent cell cytotoxicity, antibody Fc receptor expression, and human immunodeficiency virus infectivity. RESULTS: Significant suppression of NKCC was observed at 2 and 24 h after the onset of intravenous morphine exposure. Suppression of NKCC persisted for 24 h after termination of morphine infusion in a "high"-dose study group. gamma-Interferon-stimulated NKCC and antibody-dependent cell cytotoxicity were also decreased after 24 h of intravenous morphine exposure. No effect on Fc receptor expression was observed. Mean virus antigen production after lymphocyte infection with human immunodeficiency virus was not increased (p24 100 ng/ml after morphine vs. 43 ng/ml before morphine; P = 0.17). CONCLUSIONS: These results suggest that morphine administration, at doses within the range of analgesic use, can cause measurable suppression of some components of the human cellular immune system.

Ultrastructural morphometric analysis of peripheral nerves after intraoperative irradiation.

Intraoperative irradiation (IORT) is used to enhance local tumour control by using large, single doses while removing critical structures from the treatment field. Peripheral nerve remains a dose-limiting normal tissue that often cannot be removed from the field. To assess ultrastructural changes in canine sciatic nerve after IORT, computerized morphometric analysis of plastic sections and electron micrographs of nerve cross-sections was used. Surgically exposed sciatic nerves were irradiated with 6 MeV electrons to 12, 20 or 28 Gy. Twelve months after treatment dogs were killed humanely and the nerves from three dogs per dose group, including non-irradiated controls, were analyzed. Twelve months after 28-Gy IORT a significant decrease in nerve fiber density occurred. Nerve fiber loss was particularly prominent in the central portion of the nerve predominantly among large nerve fibers. Other nerve fiber parameters including fiber and axon area, diameter and perimeter, myelin thickness, form factor (measure of roundness), and G ratio (axon diameter/fiber diameter) did not show significant, dose-related changes. An increase in microtubule and neurofilament density in irradiated nerve axons was found. These changes are suggestive of radiation-induced hypoxia (damage to microvasculature) resulting in axon damage and subsequent nerve fiber loss as a possible mechanism of late radiation injury to peripheral nerve.

Long-term morbidity following jejunoileal bypass. The continuing potential need for surgical reversal.

OBJECTIVE: To review the late sequelae of jejunoileal bypass (JIB) and the potential role of late surgical reversal in ameliorating morbidity and mortality following JIB. DESIGN: Patients who underwent JIB between 1965 and 1977 were contacted and pertinent health-event information was gathered. Early sequelae were defined as disorders occurring within the first 2 years after JIB; late sequelae were those occurring after 2 years. Health events occurring between 0 and 23 years after JIB were documented. SETTING: A private, tertiary referral center. PATIENTS: Patients underwent JIB for morbid obesity that had failed medical and/or psychiatric interventions. MAIN OUTCOME MEASURES: Body mass index (BMI) (weight kilograms divided by the square of the height in meters), diarrhea, electrolyte imbalance, acute, and chronic liver disease, renal disease, JIB reversal, reason for JIB reversal, death, and cause of death. RESULTS: A total of 453 morbidity obese patients underwent JIB. By 2 years following JIB, the mean (+/- SD) BMI dropped from 49.3 +/- 8.1 to 31.1 +/- 0.8 and remained at this level until year 15, after which weight gradually increased (BMI, 35.4 +/- 3.1). The most severe early complication was acute liver failure, which occurred in 7% of patients and caused seven deaths. At 15 years, the actuarial probability of the most common serious late complications related to JIB were renal disease (37%), with two deaths; diarrhea (29%); and liver disease (10%), with three deaths. One hundred thirty-eight patients (31%) had a bypass reversal. The most common indications for reversal were diarrhea and electrolyte disturbance (29%), renal disease (19%), and liver disease (17%). Fifty-six patients died more than 30 days after JIB: 64% before JIB reversal, 13% at the time of reversal, and 23% subsequently. CONCLUSIONS: Jejunoileal bypass is associated with progressive accrual of serious, sometimes life-threatening complications. Lifelong follow-up for early diagnosis and surgical reversal before life is threatened should reduce the morbidity and mortality associated with this procedure.

Effects of intraoperative hyperthermia on canine sciatic nerve: histopathologic and morphometric studies.

Failure to achieve local control in the treatment of pelvic and retroperitoneal tumours results in a high rate of recurrences. The objective of intraoperative hyperthermia (IOHT) is to enhance the effect of intraoperative radiation therapy and to increase local tumour control. The tolerance of peripheral nerves to heat may limit the heat dose that can be applied to tumours. Histopathologic and histomorphometric changes of canine sciatic nerve after 60-min IOHT were studied in three groups of five dogs each for temperatures of 43, 44 and 45 degrees C. IOHT was performed using a water-circulating hyperthermia device with a multichannel thermometry system on surgically exposed sciatic nerve. Histopathologic and histomorphometric studies were done immediately, 3 weeks and 12 months after IOHT. Histologic changes observed immediately after treatment were minimal but at 3 weeks following 60-min 45 degrees C IOHT both axon and myelin loss and an increase in endoneurial fibrous tissue were observed. Twelve months after treatment a statistically significant decrease in axon, myelin and small vessel percentages as well as an increase in endoneurial and epineural connective tissue were observed for dog treated to 45 degrees C. Dog treated to 44 degrees C for 60 min had similar statistically significant but less severe changes. Twelve months after 43 degrees C IOHT for 60 min, nerve fibres appeared normal and endoneurial connective tissue was only increased mildly around small and medium-sized vessels. These results suggest that temperatures to the peripheral nerve > 44 degrees C for 60 min are likely to cause significant histopathologic changes that can be found 12 months after treatment. A hypothesis of the mechanism of heat injury to peripheral nerves was developed.

A clinical trial of antioxidant vitamins to prevent colorectal adenoma. Polyp Prevention Study Group.

BACKGROUND: People who consume a diet high in vegetables and fruits have a lower risk of cancer of the large bowel. Antioxidant vitamins, which are present in vegetables and fruits, have been associated with a diminished risk of cancers at various anatomical sites. We conducted a randomized, controlled clinical trial to test the efficacy of beta carotene and vitamins C and E in preventing colorectal adenoma, a precursor of invasive cancer. METHODS: We randomly assigned 864 patients, using a two-by-two factorial design, to four treatment groups, which received placebo; beta carotene (25 mg daily); vitamin C (1 g daily) and vitamin E (400 mg daily); or the beta carotene plus vitamins C and E. In order to identify new adenomas, we performed complete colonoscopic examinations in the patients one year and four years after they entered the study. The primary end points for analyses were new adenomas identified after the first of these two follow-up examinations. RESULTS: Patients adhered well to the prescribed regimen, and 751 completed the four-year clinical trial. There was no evidence that either beta carotene or vitamins C and E reduced the incidence of adenomas; the relative risk for beta carotene was 1.01 (95 percent confidence interval, 0.85 to 1.20); for vitamins C and E, it was 1.08 (95 percent confidence interval, 0.91 to 1.29). Neither treatment appeared to be effective in any subgroup of patients or in the prevention of any subtype of polyp defined by size or location. CONCLUSIONS: The lack of efficacy of these vitamins argues against the use of supplemental beta carotene and vitamins C and E to prevent colorectal cancer. Although our data do not prove definitively that these antioxidants have no anticancer effect, other dietary factors may make more important contributions to the reduction in the risk of cancer associated with a diet high in vegetables and fruits.

Intraoperative radiation (IORT) injury to sciatic nerve in a large animal model.

Peripheral nerve appears to be a dose-limiting normal tissue in the clinical application of intraoperative radiation therapy (IORT). To assess IORT injury to peripheral nerve, three groups of five beagle dogs received doses of 12, 20 or 28 Gy to the surgically exposed and isolated right sciatic nerve in the mid-femoral region using 6 MeV electrons. The left sciatic nerve of each dog served as its own control. As a surgical control five dogs received surgical exposure of the nerve only. Monthly neurologic exams, electromyogram and nerve conduction studies were performed following treatment for 12 months. After that dogs were euthanatized and histologic studies of nerves were done to define the degree of axon and myelin loss as well as presence of fibrosis and vascular lesions for different doses of IORT. Results showed that the threshold dose most likely related to expression of severe radiation damage to the nerve in this model is between 20 and 25 Gy. Radiation injury to peripheral nerve appears to be the result of direct radiation effects on Schwann cells and nerve vasculature and secondary effects resulting from damage to regional muscle and vasculature. A theoretical mechanism of radiation injury to peripheral nerve is proposed.

Perioperative immunomodulation in cancer surgery.

Despite undergoing a curative resection, many patients with colorectal cancer will develop and die of metastatic disease. It has been shown clinically and experimentally that surgery causes a transient period of immunosuppression, and it is postulated that this may encourage both the implantation of surgically disseminated tumor cells and the growth of existing micrometastases. The present study used natural killer cell cytotoxicity (NKCC) and tumor burden to evaluate perioperative modulation of immunocompetence in a murine model. We measured NKCC and tumor burden responses to a standardized surgical stress (SSS) alone, and to either morphine sulfate (MS) (15 mg/kg subcutaneously x 4 doses), ketorolac (a prostaglandin synthetase--prostaglandin E2--inhibitor) (2.5 mg/kg subcutaneously x 4 doses), or interleukin 2 (2,000 units intraperitoneally x 3 doses) administration with the SSS. In this model, we found that both low-dose interleukin-2 (IL-2) and ketorolac reversed the NKCC suppression associated with surgery, whereas morphine resulted in further depression of NKCC. In addition, IL-2 significantly decreased tumor incidence, whereas continuous MS exposure markedly increased tumor burden after surgery. These data suggest that IL-2 and ketorolac may be effective agents for the restoration of perioperative immune competence, whereas the use of continuous morphine might have significant deleterious effects.

Effects of intraoperative hyperthermia on peripheral nerves: neurological and electrophysiological studies.

The tolerance of peripheral nerves to heat may limit the heat dose which can be applied to tumours. This may be particularly important in intraoperative hyperthermia (IOHT) for pelvic and retroperitoneal tumours. Furthermore the effects of hyperthermia alone must be known before its effects can be assessed in combination with irradiation. In this study injury to sciatic nerves was evaluated in 30 beagle dogs for 1 year following IOHT. IOHT was performed using a water circulating hyperthermia device with multichannel thermometry system. Neurological and electrophysiological examinations were done before, during and after IOHT treatment. Electrophysiological examinations showed a significant decrease in sciatic nerve conduction velocity and potential amplitude immediately after 60 min of heating for all temperatures. The greatest decrease in conduction velocity was observed for a temperature of 45 degrees C. Full recovery of nerve conduction velocity was observed 3 weeks following hyperthermia for all dogs except for those exposed to 45 degrees C. Neurological findings correlated with electrophysiological results. All five dogs which had nerve exposed to 45 degrees C for 60 min had severe neurological changes, with recovery taking place between 3 and 11 months after treatment. Based on these results it appears that temperatures to the peripheral nerve exceeding 44 degrees C for 1 h are likely to cause significant, but not necessarily permanent, nerve injury.

Performance of an adaptive MIMO controller for a multiple-element ultrasound hyperthermia system.

A prototype adaptive automatic control algorithm was implemented to regulate temperatures measured at several points in a tumour by adjusting the power applied to several ultrasound transducers. The goal was to control the temperatures under the elements of a mosaic applicator individually without any priori knowledge of which probes are under which elements. The control algorithm was devised for clinical applications where the position of each probe with respect to the heat sources is difficult to determine precisely. Instead, the program 'learns' the relationship between the inputs (power levels) and the outputs (temperatures) automatically. Based on the observed transfer function relating the power at m sources to the temperatures n probes, where n and m are not necessarily the same, a new method was used to implement a feedback controller. This method simplifies the design of the controller for a multiple-input/multiple-output (MIMO) system, while taking into account the coupling that may exist between the various elements of the system. As a result of using an adaptive scheme, the regulator continuously tracks changes in the system, such as blood flow variations or patient motion, by modifying its control parameters. The algorithm performance has been tested in simulations as well as experiments in dog thigh and a perfused kidney model.

The MEE/PEE ratio as a predictor of excess weight loss for up to 1 year after vertical banded gastroplasty.

Thirteen morbidly obese individuals were studied prospectively for 1 year after vertical banded gastroplasty (VBG) to determine the relationships between energy balance equation parameters and excess weight loss. The measured energy expenditure (MEE), as determined by indirect calorimetry, was not correlated with weight loss. However, when this parameter was expressed as a ratio to the predicted energy expenditure (PEE), the ratio was significantly correlated with the postoperative excess weight loss at 2, 6, and 12 months. The mean daily energy intake after the VBG was 2715 +/- 865 kJ. The postoperative energy intake was not correlated with the excess weight loss. Diet-induced thermogenesis was studied in eight patients. The mean diet-induced thermogenesis was 10.31% +/- 13.92%. The diet-induced thermogenesis was not correlated with the postoperative excess weight loss. The preliminary findings of this trial suggest that the MEE/PEE ratio is useful in predicting excess weight loss after VBG.

Techniques for intraoperative hyperthermia with ultrasound: the Dartmouth experience with 19 patients.

Over the course of 3 years, tumours of 19 patients were heated with ultrasound in the operating room during surgical resection. Immediately following intraoperative radiation therapy, thermocouples were inserted into tumour and adjacent normal structures. Patients were then given a 60-min heat treatment with ultrasound after a 10-15-min heatup period. Temperatures were measured at a total of 133 fixed locations for the 19 patient series. Temperature mapping was done in the tumour volume when logistically feasible. Treatment sites included colorectal (n = 3), portahepatus (n = 1), pancreas (n = 7), liver (n = 1), pelvis (n = 3), sacrum (n = 2), and abdomen (n = 2). A sterile, constant-volume water circulating system was utilized to control surface temperatures. Three generations of completely immersible transducers were designed over the course of this study with a 4-cm height specification. Since the ultrasound transducer was assembled on the sterile field during surgery, a 1, 2 or 3 MHz ceramic element was placed in either a 6, 8 or 10 cm diameter aluminium housing to conform the acoustic field to the tumour size. Average of the maximum temperatures attained was 46.6 degrees C. Temperature with which 90% of all measured points equalled or exceeded (T90) was 39.2 degrees C. The T50 was 42.9 degrees C. This compared favourably with T90 and T50 of 38.8 and 41.9 degrees C, respectively, in our outpatient clinic series, in which superficial tumours were treated with a similar external applicator, and patient tolerance was often a treatment limitation.

Analysis and testing of a concentric ring applicator for ultrasound hyperthermia with clinical results.

A planar ultrasound transducer was modified by etching concentric circles on one surface of a piezoelectric ceramic to create four rings. The 10 cm diameter transducer had four active rings and an unenergized centre. The transducer housing was designed to be completely immersed in fluid, suitable for intraoperative hyperthermia. The transducer was resonant at 1.0 MHz and was tested in a water tank and in an acoustic absorbing medium where the steady-state temperatures were measured. A comparison between a single 10 cm element and the concentric ring modification with all rings at equal power density showed the performance to be nearly identical. In vivo experiments in canine thigh verified the phantom predictions as individual rings were energized. Theoretical intensity calculations were made and compared favourably to water tank test results. Clinical hyperthermia treatments for chest wall and head and neck tumours showed that the temperature distribution could be highly modified by adjusting the power to individual rings while holding the transducer stationary. Automated temperature mapping parallel to the transducer face was used to compare a single element applicator to the concentric ring applicator in clinical treatments on the same lesion. The concentric ring applicator was radially adjustable and was found to be advantageous in lowering the central peak temperatures and flattening the temperature distribution in tumours. A comparison between the single element clinical and operating room series showed that when pain is removed as a treatment limiting factor, higher central tumour temperatures are possible and more of the tumour volume achieves therapeutic temperatures. The concentric ring design improves the temperature distribution such that the higher central temperatures will not be necessary.

Effect of morphine on growth of metastatic colon cancer in vivo.

Control of colon cancer depends, in part, on intact immune defense mechanisms. Since opiates are known to affect some components of immune function, this study was conducted to determine the effect of high-dose subcutaneous morphine sulfate and of low-dose intrathecal morphine on the postoperative growth of metastatic colon cancer. Five groups of 15 Fischer 344 rats were given intraportal injections of colon cancer cells as follows: group 1, control; group 2, daily subcutaneous injections of 20-mg/kg morphine the day before and for 2 days after colon cancer cell inoculation; group 3, daily subcutaneous injections of saline; group 4, daily intrathecal injections of 20 micrograms of morphine; and group 5, daily intrathecal injections of saline. There was a significant decrease in the hepatic tumor burden in group 2 compared with groups 1 and 3 and a significant increase in the hepatic tumor burden in groups 4 and 5 compared with group 1. This study demonstrates that intermittent injections of a narcotic may decrease the growth of tumor cells that gain access to the circulation during a surgical procedure. In addition, the results support the concept that tumor cells entering the circulation during a vulnerable period of postoperative immunosuppression are more likely to survive as metastatic tumor.