David Fromm

An apoptotic response to photodynamic therapy with endogenous protoporphyrin in vivo

CDF1 mice bearing the colon-26 tumor were treated with aminolevulinic acid (200 mg kg-1) by tail-vein injection, with tumor sites irradiated 4 h later at 633 nm (75-120 J cm-2). 10 h after irradiation, samples of tumors were removed for histology studies and analysis of DNA fragmentation by static gel electrophoresis. The resulting patterns indicate an apoptotic response to photodynamic therapy with endogenously formed protoporphyrin.

Upper GI bleeding in an urban hospital: Etiology, recurrence, and prognosis

Acute upper gastrointestinal bleeding (UGIB) continues to be a common cause of hospital admission and morbidity and mortality. This study reviews 469 patients admitted to a surgical service of an urban hospital. There were 562 total admissions because 53 patients were readmitted 93 times (recurrence rate, 20%). The most common causes of bleeding, all endoscopically diagnosed, included acute gastric mucosal lesion (AGML) (135 patients, 24%), esophageal varices (EV) (121 patients, 22%), gastric ulcer (108 patients, 19%), duodenal ulcer (78 patients, 14%), Mallory-Weiss tear (61 patients, 11%), and esophagitis (15 patients, 3%). Nonoperative therapy was sufficient in 504 cases (89.5%). Endoscopic treatment was used in 144 cases. Operations were performed in 58 cases (10.5%), including 29% of ulcers. Emergency operations to control hemorrhage were required in only 2.5% of all cases. The rate of major surgical complications was 11% and the mortality rate was 5.2%. There were 58 deaths (12.6%), with 36 deaths directly attributable to UGIB. Factors correlating with death include shock at admission (systolic blood pressure less than 80), transfusion requirement of more than five units, and presence of EV (all p less than 0.001). Most cases of UGIB can be treated without operation, including endoscopic treatment, when diagnostic endoscopy establishes the source. Subsequent operation in selected patients can be done with low morbidity and mortality rates.

Current Concepts in Gastrointestinal Photodynamic Therapy

OBJECTIVE To review current concepts of photodynamic therapy (PDT) applied to the treatment of tumors of the gastrointestinal tract. SUMMARY BACKGROUND DATA PDT initially involves the uptake or production of a photosensitive compound by tumor cells. Subsequent activation of the photoreactive compound by a specific wavelength of light results in cell death, either directly or as a result of vascular compromise and/or apoptosis. METHODS The authors selectively review current concepts relating to photosensitization, photoactivation, time of PDT application, tissue selectivity, sites of photodynamic action, PDT effects on normal tissue, limitations of PDT, toxicity of photosensitizers, application of principles of PDT to tumor detection, and current applications of PDT to tumors of the gastrointestinal tract. RESULTS PDT is clearly effective for small cancers, but it is not yet clear in which cases such treatment is more effective than other currently acceptable approaches. The major side effect of PDT is cutaneous photosensitization. The major limitation of PDT is depth of tumor kill. As data from current and future clinical trials become available, a clearer perspective of where PDT fits in the treatment of cancers will be gained. Many issues regarding pharmacokinetic data of photosensitizers, newer technology involved in light sources, optimal treatment regimens that take advantage of the pharmacophysiology of photoablation, and light dosimetry still require solution. One can foresee application of differing sensitizers and light sources depending on the specific clinical situation. As technologic advances occur, interstitial PDT may have significant application. CONCLUSIONS PDT has a potentially important role either as a primary or adjuvant mode of treatment of tumors of the gastrointestinal tract.

Hemodynamic effects of 5-aminolevulinic acid in humans

Endogenous protoporphyrin IX (PpIX), which results from the oral administration of 5-aminolevulinic acid (ALA), is being investigated for its efficacy as a photosensitizing agent for photodynamic therapy (PDT). Clinical use of ALA has been associated with only mild gastrointestinal side effects. The hemodynamic effects of orally administered ALA in doses used for PDT are unknown. Six patients with a significant history of cardiac disease underwent Swan-Ganz catheterization prior to ALA administration and abdominal operation for PDT. Hemodynamic data collection began at least 1 h prior to ALA, and continued for at least 4 h subsequently, during which time no other medications were administered. When compared to measurements made prior to ALA administration, all patients displayed a significant decrease in systolic and diastolic blood pressures, pulmonary artery systolic and diastolic pressures as well as pulmonary vascular resistance. Five of the six patients also developed a decrease in systemic vascular resistance. No significant changes in pulmonary capillary wedge pressure, cardiac output or cardiac index was observed, but the mean pulse rate rose significantly. These findings cannot be explained on the basis of other cardiovascular depressants or to poor central volume status. Although no adverse sequela were appreciated as a result of the observed hemodynamic changes, this potential should be recognized in patients undergoing PDT using ALA.

On-line fluorescence of human tissues after oral administration of 5-aminolevulinic acid

It is important to have a frame of reference for the timing of photodynamic therapy (PDT) using 5-aminolevulinic acid (ALA) so that PDT can occur when the tissue levels of protoporphyrin IX (PP) are at a maximum. This study describes a non-invasive fluorescence technique for detecting tissue PP levels after systemic ALA administration in patients with gastrointestinal cancer. The data suggest that the intensity of tumor surface fluorescence correlates with the tumor PP concentration. Spectrophotofluorometric measurements of skin and buccal mucosa also offer an easily acquired and rapid means for determining changes in plasma concentrations of PP. A number of potential variables, including blood flow, affect the intensity of fluorescence. We report that fluorescence measurements in situ are best adapted to the measurement of changes in the porphyrin levels in tissues rather than the absolute concentrations.

Tumor blood-flow changes following protoporphyrin IX-based photodynamic therapy in mice and humans.

The effects of aminolevulinic acid (ALA)-based photodynamic therapy (PDT) on tumor blood flow are controversial. This study examines the effects of ALA and Photofrin-based PDT on blood flow of Colon-26 tumors implanted in mice as well as the effects of ALA-based PDT on blood flow of human colorectal carcinomas and a carcinoid tumor in situ. Tumors are implanted in both flanks of mice. One tumor of each animal serves as a control. Blood flow is measured using a laser Doppler method. Tumor blood flow in mice not receiving a photosensitizer but treated with three different light fluences (50, 100 and 150 J/cm2) does not differ significantly from blood flow in the untreated tumor in the opposite flank. PDT after ALA administration using the three different light fluences does not significantly affect blood flow. In contrast, PDT after Photofrin administration causes a significant decrease in tumor blood flow with each light fluence, but this change is not as dramatic as reported in other studies. In contrast to mice, six patients who receive ALA prior to surgery all show a decrease in blood flow (mean = 51.8%, p < 0.001) after PDT using 100 J/cm2. Comparison with other published results suggests that it is likely that flow measurement by the laser Doppler method underestimates the effects of PDT on tumor blood flow due to the depth of laser penetration. Nevertheless, the present observations on blood flow suggest that the effects of ALA-based PDT on adenocarcinomas of the colon and rectum as well as an intra-abdominal carcinoid tumor in humans are more pronounced than would be predicated by some animal studies.

Ligation of the pancreatic duct during difficult operative circumstances.

BACKGROUND The current approach to managing the distal pancreas after pancreaticoduodenectomy is to anastomose the stump to either the jejunum or stomach, but pancreatic ductal occlusion without anastomosis of the pancreatic remnant remains an option during difficult operative circumstances. This article describes some situations in which distal pancreatic ductal ligation may be of use and reviews the morbidity associated with this procedure. STUDY DESIGN Review was done of a prospectively kept database of operative and pathology reports and of both immediate and 3-month to 6-year followup data of seven patients who underwent ductal occlusion during pancreaticoduodenectomy or central pancreatectomy. RESULTS Ductal occlusion was performed in three circumstances: 1. necessity for expedient termination of the operation; 2. short jejunal mesentery allowing only a tension-free biliary or pancreatic anastomosis; and 3. massive jejunal edema that would result in a tenuous anastomosis. Two patients developed a fistula. One patient had dense residual pancreatic fibrosis, which resolved after 5 days; the other patient had a normal residual pancreas and subsequently underwent a pancreaticojejunostomy. Three patients developed acute pancreatitis (two had a normal and one had mild to moderate fibrosis in the residual pancreas) and one of these developed a peripancreatic abscess and late pseudocyst. Four patients with dense fibrosis did not develop acute pancreatitis. No patient developed either overt or worsening diabetes during the limited followup. None of the patients required enzyme supplementation, but all voluntarily maintained a low-fat diet. CONCLUSIONS The development of complications after ductal ligation appears to be associated with the degree of fibrosis of the residual distal gland. Acute pancreatitis and fistula are the major complications but are associated with a low mortality. Diabetes is a potential late problem. The morbidity associated with ductal ligation is generally accepted as being greater than anastomosis, but ligation can be considered as an alternative in difficult circumstances where anastomosis of the distal pancreatic stump is believed to be unwise.

Effects of fractionated 5-aminolevulinic acid administration on tissue levels of protoporphyrin in vivo.

The photodynamic therapy (PDT) of malignant tissues can be achieved via the administration of 5-aminolevulinic acid (ALA), which is naturally converted to the photoreactive substance protoporphyrin IX (PP). This study compares bolus with fractionated ALA dosing in order to determine whether one of these methods results in a higher tissue concentration of PP. Mice bearing a subcutaneously implanted colon-26 tumor were treated with ALA (200 mg kg-1), given intravenously either as a single bolus or as three equally divided doses at 50 min intervals. Tissue samples of tumor, kidney, skin, liver, skeletal muscle, colon and plasma were obtained 2, 3, 4 and 6 h later for the analysis of PP concentrations. Fractionated dosing results in significantly higher concentrations of PP at 4 and 6 h for kidney, 3 and 6 h for skin, 3 h for colon and 6 h for liver. In contrast, fractionated dosing has no significant effect on the PP concentrations of muscle and plasma. Fractionated dosing results in a significantly greater PP concentration in the tumor at 3 h relative to that observed for the bolus dose. However, from a consideration of the time of PP measurement, it is concluded that fractionated dosing may not cause a significant increase in the PP concentration in colon-26 tumors relative to that observed for the bolus dose.

STUDIES ON 2-DEOXY-D-GLUCOSE-INDUCED HYPERGLYCEMIA.

Summary Small doses of 2-deoxy-D-glucose were injected into the pancreatoduodenal artery or into the femoral vein of normal dogs. The route of administration did not markedly affect the intensity and duration of the hyperglycemic response. The response was prevented by pre-treatment with dihydroergotamine. It is concluded that 2-DG does not stimulate the release of glucagonlike materials from the pancreas and that, probably, the observed hyperglycemia was due to secretion of epinephrine and inhibition of glucose utilization. No evidence of insulin release was obtained in these experiments.

Toward a more perfect society

ConclusionI have touched on the following points: perpetuation of the spirit of DDW, membership expansion, innovation in our annual meeting, greater membership input, fertilization of the bed-bench breeding ground, support from industry, establishment of a research foundation, strategic planning for our journal, and the setting of standards. I have also asked some questions: Do we want more uniform standards of practice? Do we insist on a more rigorous evaluation of technology? How lofty a standard do we wish to achieve? Are we asking the right clinical questions? We must actively participate in and contribute to the future of surgery of the alimentary tract so that we are indeed among the best. All of us are proud to be members of the SSAT. Now and in the future we can state with progressively greater pride that we are members of the best surgical organization devoted to the alimentary tract because we swim harder and we are becoming the lead dogs!