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.

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.

Intraoperative interstitial microwave-induced hyperthermia and brachytherapy.

Intra-operative placement of 11-gauge nylon catheters into deep-seated unresectable tumors for interstitial brachytherapy permits localized heating of tumors (hyperthermia) using microwave (915 MHz) antennas which are inserted into these catheters. Four preliminary cases are described where epithelial tumors at various sites were implanted with an antenna array and heated for 1 hour, both before and after the iridium-192 brachytherapy. Temperatures were monitored in catheters required for the appropriate radiation dosimetry but not required for the interstitial microwave antenna array hyperthermia (IMAAH) system. Additional thermometry was obtained using nonperturbed fiberoptic thermometry probes inserted into the catheters' housing antennas. No significant complications, such as bleeding or infection, were observed. This approach to cancer therapy is shown to be feasible and it produces controlled, localized hyperthermia, with temperatures of 50 degrees C or more in tumors. This technique may offer a therapeutic option for pelvic, intra-abdominal and head and neck tumors.

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.

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.

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.

Radioiodine total body scan versus serum thyroglobulin levels in follow-up of patients with thyroid cancer.

Two groups of patients were studied to compare the efficacy of serum thyroglobulin (Tg) levels to 131I total body scans in the follow-up of patients with thyroid cancer. All of the group of 30 patients without recurrence had undetectable Tg levels on and off thyroid hormone replacement, and all had negative total body scan results although eight patients showed uptake in remnant thyroid tissue. In the second group of 37 patients with documented recurrent or metastatic disease, 34 (92%) had positive serum Tg levels, although the levels in five of these patients were undetectable while on thyroid replacement, and 31 (84%) had positive total body scan results. The false negative results of the two tests were not overlapping, and of those with positive Tg levels, 29 showed a significant increase once thyroid hormone therapy had been withdrawn. We conclude that although the percentages of positive Tg levels and body scan results in patients with recurrent disease are similar, both tests are required to minimize the number of patients with undiagnosed metastases. Second, thyroid-stimulating hormone suppression has a definite although unpredictable effect on serum Tg levels in patients with thyroid cancer, and thyroid hormone should be withdrawn prior to measurement of serum Tg to minimize the number of false negative results.

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.

Chemoprevention of colorectal neoplasms. Ascorbic acid and beta-carotene.

The organospecific, 1,2-dimethylhydrazine-induced rat tumor model was used to test tumor formation in groups of animals receiving regular chow, powdered chow with 7%/wt ascorbic acid supplement, pelleted chow with 1%/wt beta-carotene supplement, and pelleted chow with placebo beadlets. Following a 16-week induction period, animals were killed and tumor formation was recorded. Tumor formation in the ascorbic acid supplement group was found to be significantly less than the control group. The beta-carotene group showed no difference in tumor formation compared with the placebo-beadlet control group. Tumor incidence was generally the same between the two control groups, and the ascorbic acid group had significantly fewer tumors than the beta-carotene group. In sum, ascorbic acid supplements in high doses significantly decreased tumor formation, whereas beta-carotene supplements in moderately high doses had no effect on tumor formation in this model.

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.

Antioxidants vs carotenoids. Inhibitors or promoters of experimental colorectal cancers.

The organospecific, 1,2-dimethylhydrazine-induced murine tumor model was used to test the effects on tumor formation of the following dietary supplements: (1) ascorbic acid, 7% per weight; (2) alpha tocopherol, 1% per weight; (3) beta carotene, 1% per weight; and (4) canthazanthin, 1% per weight. Following a four-week dietary acclimation, a 16-week 1,2-dimethylhydrazine induction, and a four-week hiatus, the animals were killed, underwent autopsies, and tumor formation was recorded. The antioxidant supplements of ascorbic acid and alpha tocopherol resulted in a significant decrease in tumor formation when compared with control groups. In contrast, the beta carotene group showed no difference in tumor formation, and canthazanthin, a non-provitamin A carotenoid, resulted in an increase in tumor formation when compared with controls. In addition, the K-gel powder control diet (a carrier medium for alpha tocopherol acetate) had a significantly higher rate of tumor formation than the regular chow and placebo beadlet control diets. In sum, ascorbic acid and alpha tocopherol demonstrated a clear chemopreventive effect, whereas beta carotene had no effect, and canthazanthin appeared to function as a promoter in this organospecific tumor model.

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.

Intraoperative radiation therapy and hyperthermia. Morbidity and mortality from this combined treatment modality for unresectable intra-abdominal carcinomas.

This is a report of a phase I trial of intraoperative radiation therapy in combination with intraoperative hyperthermia for the treatment of locally advanced, unresectable intra-abdominal carcinomas. Using an ultrasound transducer system specifically designed for intraoperative applications, 19 patients have been successfully treated, demonstrating the feasibility of this combination modality. The morbidity (58%) and mortality (11%) rates reported in this series are comparable to rates reported in series of similar patients receiving intraoperative radiation therapy alone. There is still a great need for considerable technological development to enable the use of intraoperative hyperthermia to treat large, complexly shaped intra-abdominal tumors, and phase II and III trials of this combination treatment modality should be performed.

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.

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.

Surgical treatment of parathyroid disease: a review.

Since the first parathyroidectomy was performed by Mandl in 1925, there have been many advances in our understanding of the parathyroid gland and its related disorders of calcium homeostasis. Our ability to establish the diagnosis of parathyroid neoplasia and locate the source of autonomous parathormone production has also dramatically improved. Nevertheless, it was the advent of the routine calcium and phosphate screening done on the sequential multiple analyzer (SMA-12) that has caused a tremendous increase in the number of patients who are diagnosed to have hyperparathyroidism and who therefore present for surgical treatment. Essential for successful and uncomplicated treatment of this disorder is a thorough understanding of the anatomy, physiology, and pathology of the parathyroid glands. This review will consider the parathyroid glands in their normal state, as well as the diagnosis and management of the various disorders associated with them.

Early colonic dysplasia: comparison of differential mucin staining and tritiated thymidine labeling.

Controversy has arisen regarding the interpretation and significance of histochemical changes in the mucin produced by the globlet cells in colonic mucosa. The shift from sulfomucin to sialomucin, which is readily identified utilizing high iron diamine-alcian blue staining techniques, has been alternately interpreted as a specific, early dysplastic and premalignant change or a nonspecific generalized response to trauma and inflammation, among others. An attempt to clarify this issue was made by comparing mucin changes identified by high iron diamine-alcian blue staining techniques with increases in DNA synthetic activity identified utilizing autoradiographic analysis of tritiated thymidine uptake. Male Holtzman rats were treated with 15 weekly subcutaneous injections of dimethylhydrazine (30 mg/kg per week) (10 rats) or placebo (10 rats). The colons were prepared and fixed, sequential sections were stained with hematoxylin-eosin or high iron diamine-alcian blue, autoradiography was performed. Analyses of labeling index showed no difference in normal background crypts between the control and treatment groups nor in crypts adjacent to those displaying abnormal mucin staining. Crypts with abnormal mucin production (sialomucin dominant) had significantly higher labeling indexes when compared with those of control animals (p less than 0.005). These findings indicate that the shifts in mucin production identified with high iron diamine-alcian blue staining represent crypts with increased and abnormally distributed mitotic activity that is an early dysplastic response to the carcinogenic stimulus.

Efficacy of differential mucin staining for predicting synchronous and metachronous colorectal carcinomas.

Despite the controversy regarding the significance and usefulness of histochemically differential mucin staining as a marker for colorectal neoplasms, some investigators have used this technique to help define those persons at risk for development of recurrent colorectal carcinoma. To further evaluate the efficacy of this method, we reviewed 85 surgical specimens of the colon and rectum using a high iron diamine-alcian blue staining technique. The group studied included 73 patients with synchronous or metachronous carcinomas and adenomas and 12 patients with no recurrence for more than 5 years who had undergone adequate follow-up, including physical examination; evaluation of serum chemistry findings; and colonoscopy, barium enema, or both. Evaluation of Dukes' staging (A and B1 versus B2 and C2) and distance of the resection margins from the tumor (less than 5 cm versus 5 cm or more) showed no correlation with the amount of sialomucin present. Resection margins from patients with either synchronous or metachronous carcinomas had significantly higher sialomucin ratios than the group without recurrence, whereas those with synchronous or metachronous adenomas did not. The false-negative rate was 4 percent (1 of 23 specimens) and the false-positive rate, 42 percent (5 of 12 specimens). We conclude that this method for evaluating resection margins of colorectal cancer specimens with differential mucin staining is highly reliable for predicting the population with synchronous and metachronous colorectal carcinomas.

Fine needle cytologic diagnosis of thyroid nodules. Review and report of 300 cases.

Three hundred patients with thyroid nodules were evaluated with fine needle biopsy and cytologic evaluation. Nineteen of 23 cancers were diagnosed by fine needle biopsy alone, for a yield of 83 percent. Four of 300 diagnoses (1 percent) were false-positive, and the evidence of neoplasm at operation was 68 percent. We believe that fine needle biopsy will greatly decrease the number of unnecessary thyroid resections.

Impact of modern diagnostic methods on the management of active rectal bleeding. Ten year experience.

We analyzed 178 patients admitted with a diagnosis of lower gastrointestinal hemorrhage from 1970 to 1979. Fifty-four percent had a subsequent or previous episode of bleeding and 78 percent required transfusions. One hundred eighteen patients had rigid sigmoidoscopy, with positive findings in 10 (8.5 percent); 98 underwent angiography, with positive findings in 41 percent; and 58 underwent colonoscopy, with positive findings in 48 percent. Comparison of these tests when the patient had active bleeding revealed the rates of positive findings for angiography and colonoscopy to be 42 and 85 percent, respectively. Sixty-five patients underwent operation and 16 eventually died, for a mortality rate of 25 percent. There was a higher percentage of deaths among patients with nondirected than in those with directed operations (32 versus 22 percent). Patients with lower gastrointestinal bleeding should undergo aggressive diagnostic evaluation utilizing sigmoidoscopy, angiography, and colonoscopy to increase the number of directed operations and decrease mortality and operative morbidity.