John Webber

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.

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.

Prophylactic laparoscopic gastrectomy for hereditary diffuse gastric cancer: A case series in a single family

This study suggests that a laparoscopic approach for prophylactic total gastrectomy for carriers of CDH1 gene mutation can be performed safely and effectively.

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.

Combined endoscopic and laparoscopic approach to a gastroesophageal tumor

Minimally invasive techniques may be used in combination to manage difficult problems in general surgery leading to shorter hospital stays and improved patient satisfaction.

Organ failure in the obese adipocytes prime polymorphonuclear cell inflammation under stress conditions.

BACKGROUND Obesity is associated with a higher risk of remote organ failure after shock and trauma. The mechanism(s) is poorly understood. Polymorphonuclear cell (PMN) inflammatory responses are important in the pathogenesis of organ injury following shock. Morbid obesity is a low-grade inflammatory state associated with proinflammatory mediator production from adipose tissue. We hypothesized that adipose tissue may modulate PMN inflammatory potential and is dependent on the magnitude of the injury-related stress response. This was studied in an in vitro model. METHODS Adipose-derived stem cells (ADSCs) conditioned to behave as mature adipocytes were incubated with physiologic and stress concentrations of adrenaline for 12 hours, and cell culture supernatants were obtained. PMNs from normal human volunteers were cocultured with the ADSC supernatants (priming) followed by addition of 1-&mgr;M fMLP (activation). PMNs alone served as control. PMN activation was indexed by superoxide anion (O2−) production, elastase release (%) and CD11b expression (mean fluorescent intensity). RESULTS Physiologic and stress levels of adrenaline resulted in significantly increased PMN activation in the presence or absence of adipocytes. However, the largest increase was noted in PMNs exposed to ADSC culture supernatants that had been cocultured with stress levels of adrenaline for 12 hours, twofold increase in CD11b expression and fourfold increase in superoxide anion and percent elastase release. CONCLUSION Adipocyte-derived mediators prime PMNs in vitro. There was a graded PMN response to adrenaline concentration with or without adipocytes in these experiments. The most profound increase in PMN inflammatory potential was noted with the adipocyte supernatant + stress adrenaline group. The clinical impact of obesity on remote organ injury is likely dependent on patient body mass index and the injury-related sympathetic responses. These data suggest a potential role for &bgr; blockade in this patient population.

Appendectomy in the Gynecological Setting: Intraoperative Findings and Corresponding Histopathology

Background/Aims: To evaluate the intraoperative findings and corresponding histopathology associated with appendectomies performed during benign gynecological surgery. Methods: Retrospective case series. Results: Twenty-two appendectomies were performed from 2002 through 2008 at Hutzel Women’s Hospital due to intraoperative findings of inflammation or erythema (n = 8), periappendiceal adhesions (n = 5), injury to the appendix or mesoappendix (n = 2), fecalith (n = 2), dilation of the appendix (n = 1), adnexal mass involving the appendix (n = 1), and suspected lipoma (n = 1). Final pathology was consistent with significant findings such as acute inflammation, periappendicitis, and adhesions or endometriosis involving the appendix in 68.2% of cases. Conclusion: In the benign gynecological setting, appendectomies were primarily performed due to inflammation or erythema. In the majority of cases, significant appendiceal pathology was confirmed.

Mesenteric Fibromatosis of the Small Bowel Mesentery After Gastric Bypass Surgery

Mesenteric fibromatosis poses a diagnostic and therapeutic challenge. We report a case of giant cell mesenteric fibromatosis tumor arising from the mesentery of the small intestine in a patient two years after a Roux-en-Y gastric bypass. A 47-year-old African-American female presented as a transfer from an outside institution with a large abdominal mass that was initially diagnosed as an intraabdominal cyst on computed tomography scan. The tumor was successfully excised surgically and the diagnosis of mesenteric fibromatosis tumor was confirmed on immunohistochemical analysis. To our knowledge, this is the only reported case of mesenteric fibromatosis tumor arising from the jejunojejunostomy anastomosis of the small bowel mesentery after Roux-en-Y gastric bypass surgery to treat morbid obesity.