Christoph Schick

Apoptosis as a cellular predictor for histopathologic response to neoadjuvant radiochemotherapy in patients with rectal cancer.

BACKGROUND Tumor shrinkage by preoperative radiochemotherapy (RCT) can markedly improve surgery in locally advanced (T4) rectal cancer with clear resection margins and may enable sphincter preservation in low-lying tumors. However, tumor response varies considerably, even among tumors treated according to the same protocol. If one is able to identify patients with highly radio-responsive tumors at the time of diagnosis, a selective and individualized policy of preoperative RCT might be pursued. METHODS The apoptotic index (AI), Ki-67, p53, and bcl-2 were evaluated by immunohistochemistry on pretreatment biopsies from 44 patients treated uniformly according to a prospective neoadjuvant RCT protocol (CAO/AIO/ARO-94). Treatment response was assessed histopathologically in the resected surgical specimen, using a five-point grading system. Expression of each marker was correlated with tumor response and relapse-free survival after curative surgery. RESULTS Tumors with complete (n = 3) or good (n = 28) response to RCT showed significantly higher pretreatment levels of apoptosis (mean AI: 2.06%) than tumors with moderate (n = 7), minimal (n = 5), or no regression (n = 1) from RCT (AI: 1.44%, p = 0.003). The AI was significantly related to Ki-67 (p = 0.05), but not to p53 and bcl-2 status. Tumor regression and AI best predicted relapse-free survival after combined modality treatment and curative surgery. CONCLUSION Spontaneous apoptosis in rectal cancer may serve as an important predictor of tumor regression from RCT in rectal cancer and as a significant prognosticator of relapse-free survival. Thus, this molecular marker may finally help to tailor therapy with regard to (neo-) adjuvant treatment of rectal cancer.

High Survivin Expression is Associated with Reduced Apoptosis in Rectal Cancer and May Predict Disease-Free Survival after Preoperative Radiochemotherapy and Surgical Resection

Background: Spontaneous apoptosis has been shown to predict tumor response to preoperative radiochemotherapy in rectal cancer. It remains to be elucidated, however, which genetic profile determines whether a tumor is more or less prone to apoptosis. Recently, a novel member of the inhibitor of apoptosis family, designated survivin, was identified. In the present study , we investigated the impact of survivin on tumor cell apoptosis and the risk to develop distant metastases or local failure after preoperative radiochemotherapy and surgical resection. Patients and Methods: The expression of survivin, p53, bcl-2 and the apoptotic index was evaluated by immunochistochemistry on pretreatment biopsies of 54 patients with locally advanced adenocarcinoma of the rectum. Survivin expression was correlated to clinical and histopathological markers, the levels of spontaneous apoptosis, p53 and bcl-2, as well as to disease-free survival, 5-year rates of local failure and distant disease after preoperative radiochemotherapy and surgical resection. Results: Survivin expression inversely correlated with the apoptotic index: High survivin expression was found in 56% of rectal carcinoma biopsies with a median apoptotic index of 1.22%. Conversely, low survivin expression in tumor cells was associated with a high median apoptotic index (2.29%, p=0.0001). High survivin expression also segregated with bcl-2 overexpression (65% bcl-2+ in tumors with high survivin expression as compared to 35% bcl-2+ in tumors with low survivin expression), but the difference was not statistically significant (p=0.1). Low survivin expression was significantly related to an increased disease-free survival rate (77% vs 18% at 5 years in tumors with high survivin expression, p=0.02) and to a redued risk for distant metastases (18% vs 78% at 5 years in tumors with high survivin expression, p=0.05) and local failure (6% vs 37% at 5 years in tumors with high survivin expression, p=0.07). Conclusion: An inverse correlation between survivin expression and the level of spontaneous apoptosis in pretreatment biopsies suggests that survivin strongly inhibits tumor cell apoptosis in rectal cancer. Survivin expression may provide a novel predictive indicator for disease-free survival after preoperative radiochemotherapy and surgical resection in rectal cancer.Hintergrund: Für die spontane Apoptoserate konnte eine prädiktive Bedeutung für die Tumorantwort nach präoperativer Radiochemotherapie beim Rektumkarzinom gezeigt werden. Bisher ist nicht geklärt, welches genetische Profil die Apoptosefähigkeit eines Tumors bestimmt. Kürzlich wurde das Protein Survivin als ein neues Mitglied der Inhibitor-of-Apoptosis-Familie identifiziert. In der vorliegenden Studie wurd der Einfluss von Survivin auf die Apoptoserate sowie das Fernmetastasenrisiko und die Rate lokoregionärer Rezidive nach neoadjuvanter Radiochemotherapie und Operation des Rektumkarzinoms untersucht. Patienten und Methoden: Die Expression von Survivin, p53, bcl-2 und die Apoptsoerate wurden immunhistochemisch in prätherapeutischen Biopsien von 54 Patienten mit lokal fortgeschrittenen Adenokarzinomen des Rektums bestimmt, die einheitich nach einem neoadjuvanten Radiochemotherapieprotokoll behandelt wurden. Die Survivin-Expression wurde mit klinischen und histopathologischen Markern, dem p53- und bcl-2-Index, dem Apoptoseindex, dem krankheitsfreien Überleben sowie dem Auftreten von Fernmetastasen oder lokoregionären Rezidiven korreliert. Ergebnisse: Die Survivin-Expression korrelierte invers mit dem Apoptoseindex: Bei hoher Survivin-Expression (56% aller Tumoren) betrug der mediane Apoptoseindex 1,22%, bei niedriger Survivin-Expression 2,29% (p=0,0001). Eine erhöhte Survivin-Expression war auch mit einer bcl-2-Überexpression assoziiert (65% bcl-2+ in Tumoren mit hoher Survivin-Expression, 35% bcl-2+ in Tumoren mit niedriger Survivin-Expression, p=0,1). Bei niedriger Survivin-Expression betrug das krankheitsfreie Überleben nach 5 Jahren 77%, bei hoher Survivin-Expression 18% (p=0,02). Die Fernmetastasenrate und die Rate an lokoregionären Rezidiven betrugen nach 5 Jahren bei Tumoren mit niedriger bzw. hoher Survivin-Expression: 18% vs. 78 % (p=0,05) bzw. 6% vs. 37% (p=0,07). Schlussfolgerung: Die signifikant inverse Korrelation zwischen der Survivin-Expression und der spontanen Apoptoserate in prätherapeutischen Biopsien weist darauf hin, dass Survivin beim Rektumkarzinom die Apoptose der Tumorzellen inhibiert. Die Survivin-Expression kann als neuer prädiktiver Indikator für das krankheitsfreie Überleben nach präoperativer Radiochemotherapie und Operation gelten.

Extensive surgery after high-dose preoperative chemoradiotherapy for locally advanced recurrent rectal cancer

PURPOSE: This was a pilot study of high-dose preoperative concurrent radiation and chemotherapy before extensive surgery in patients with locally advanced recurrent rectal cancer. Here we report on curative resectability, acute toxicities during chemoradiotherapy, surgical complications, local control, and three-year survival rates achieved with this aggressive multimodal regimen. METHODS: Between 1994 and 1997, 35 previously nonirradiated patients with pelvic recurrence of rectal cancer were entered in the study. All patients presented with tumor contiguous or adherent to adjacent pelvic organs and were not deemed amenable to primary curative surgery. A total radiation dose of 50.4 Gy with a small-volume boost of 5.4 to 9 Gy was delivered in conventional fractionation (single dose, 1.8 Gy). 5-Fluorouracil was scheduled as a continuous infusion of 1,000 mg/m2/day on Days 1 to 5 and 29 to 33. Six weeks after completion of chemoradiotherapy, patients were reassessed for resectability, and radical surgery was attempted whenever feasible. RESULTS: After preoperative chemoradiotherapy 28 of 35 patients (80 percent) underwent resection with curative intent. In 16 of 35 patients (57 percent) extended resection of adjacent organs was performed. Resections with negative margins were achieved in 17 patients (61 percent); 9 patients had microscopic, and 2 patients had gross residual disease. There was no postoperative mortality. Fourteen patients (44 percent) experienced postoperative complications. Toxicity from chemoradiotherapy occurred mainly as diarrhea (National Cancer Institute Common Toxicity Criteria Grade 3; 23 percent), dermatitis (Grade 3; 11 percent), and leucopenia (Grade 3; 11 percent). One patient died of tumortoxic multiple organ failure during chemoradiotherapy. With a median follow-up of 27 months, local re-recurrence after curative resection was observed in only three patients (18 percent); six patients developed distant metastases. Three-year actuarial survival rate was significantly improved after complete resection (82 percent) as compared with noncurative surgery (38 percent;P=0.03). CONCLUSION: A combination of high-dose preoperative chemoradiotherapy followed by extended surgery can achieve clear resection margins in more than 60 percent of patients with recurrent rectal tumor not amenable to primary surgery. An encouraging trend evolved for this multimodal treatment to improve long-term local control and survival rate.

Preoperative radiation with concurrent 5-fluorouracil for locally advanced T4-primary rectal cancer

Purpose: In cT4-rectal carcinoma disease-free margins often cannot be obtained by primary surgery, and even if total en bloc resection is accomplished, local failure remains high with surgery alone. Herein we report on the curative resectability rate, acute toxicities, surgical complications, local control and 5-year survival rates achieved with a more aggressive multimodality regimen, including preoperative radiochemotherapy. Patients and Methods: Between 1/1990 and 12/1998, a total of 31 patients with cT4-rectal cancer were treated at out institution. All patients presented with tumor contiguous or adherent to adjacent pelvic organs. Eight patients had synchronous distant metastases. A total radiation dose of 50.4 Gy with a small-volume boost of 5.4 to 9 Gy was delivered (single dose: 1.8 Gy). 5-FU was scheduled as a continuous infusion of 1000 mg/m2 per 24 hours on day 1 to 5 and 29 to 33. Six weeks after completion of radiochemotherapy, patients were reassessed for resectability. Results:After preoperative radiochemotherapy, 29/31 patients (94%) underwent surgery with curative intent. Resection of the pelvic tumor with negative margins was achieved in 26/31 patients (84%), 3 patients had microscopic residual pelvic disease. In 3/8 patients with distant spread at presentation a complete resection of metastases was finally accomplished. Toxicity of radiochemotherapy occurred mainly as diarrhea (NCI-CTC Grade 3: 23%), dermatitis (Grade 3: 16%) and leucopenia (Grade 3: 10%). Surgical complications appeared as anastomotic leakage in 3, wound infection in 2, fistula, abscess and hemorrhage in 1 patient, respectively. With a median follow-up of 33 months, local failure after curative resection was observed in 4 patients (19%), 3 patients (14%) developed distant metastases. The 5-year overall survival rate for the entire group of 31 patients was 51%, following curative surgery 68%. Conclusion: A combination of high-dose preoperative radiochemotherapy followed by extended surgery can achieve clear resection margins in more than 80% of patients with locally advanced cT4 rectal tumor. An encouraging trend evolves for this multimodality treatment to improve long-term local control and survival.Ziel: Bei cT4-Rektumkarzinomen ist die lokale Kontrolle und das Überleben nach alleiniger Operation unbefriedigend, eine primäre R0-Resektion oft nicht möglich. Wir analysierten die Rate an kurativen (R0) Resektionen nach präoperativer Radiochemotherapie, die Toxizität der Radiochemotherapie, die chirurgische Morbidität sowie die lokale Kontrolle und das Fünf-Jahres-Gesamtüberleben nach multimodaler Therapie. Patienten und Methodik: Von Januar 1990 bis Dezember 1998 wurden 31 Patienten mit lokal fortgeschrittenen cT4-Rektumkarzinomen behandelt. Alle Patienten wiesen Tumoren auf, die von umliegenden Organen im Becken nicht abgrenzbar oder klinisch adhärent/fixiert waren. Acht Patienten hatten synchrone Fernmetastasen. Die Gesamtdosis der Radiotherapie (Einzeldosis: 1,8 Gy) betrug 50,4 Gy + Boost von 5,4 bis 9 Gy. 5-FU wurde als 120-stündige Dauerinfusion (1000 mg/m2/d) an den Tagen 1 bis 5 und 29 bis 33 verabreicht. Sechs Wochen nach Radiochemotherapie erfolgte die Reevaluierung der Operabilität. Ergebnisse: Nach präoperativer Radiochemotherapie konnten 29/31 Patienten (94%) in kurativer Intention operiert werden, bei 26/31 Patienten (84%) wurde eine radikale Resektion (R0) des Rektumtumors erreicht, bei drei Patienten verblieb mikroskopisch ein Tumorrest (R1). Eine histologisch komplette Entfernung von Fernmetastasen gelang bei 3/8 Patienten. Die Toxizität der Radiochemotherapie bestand aus Diarrhö (NCI-CTC-Grad 3: 23%), Hauterythem (Grad 3: 16%) und Leukopenie (Grad 3: 10%). Postoperative Komplikationen traten als Anastomoseninsuffizienzen (drei Patienten), Wundinfektionen (zwei Patienten), Fistel, Abszess und Blutung (je ein Patient) auf. Bei einer medianen Nachbeobachtungsdauer von 33 Monaten sind bislang nach R0-Resektion vier Lokalrezidive (19%) aufgetreten, drei Patienten entwickelten neue Fernmetastasen (14%). Die Fünf-Jahres-Überlebensrate betrug für alle Patienten 51%, nach kurativer Operation 68%. Schlussfolgerung: Durch präoperative Radiochemotherapie und nachfolgende Operation kann bei mehr als 80% der Patienten mit initial weit fortgeschrittenen cT4-Rektumtumoren eine R0-Resektion erreicht werden. Die lokale Kontrolle und das Überleben sind für dieses multimodale Regime vielversprechend.

Differential effects of surgical sympathetic block on sudomotor and vasoconstrictor function.

Objective: To assess the effects of a surgical block of the sympathetic chain at the T2 level on vasoconstriction and palmar sweating in patients with palmar hyperhidrosis. Methods: In a prospective study, sympathetic vasoconstriction was measured by laser–Doppler imaging and by computer-assisted infrared thermography (rewarming kinetics following immersion of both hands in ice water [4 °C, 30 seconds]) in 61 patients with hyperhidrosis preoperatively and 2 days and 3 months postoperatively. In addition, palmar sweating preoperatively and 3 months postoperatively was assessed by quantitative sudometry. Results: Before surgery, rewarming kinetics was significantly slower in the patients (n = 61) than in the healthy control subjects (n = 28). Two days after the block, baseline skin temperature increased by about 5 °C, and rewarming was massively accelerated in each of the patients. Three months postoperatively, rewarming kinetics was still accelerated in 36 hands, was unchanged from the preoperative condition in 42, and had worsened in 12. These changes were accompanied by parallel alterations of laser–Doppler flux. However, palmar sweating was massively reduced in all but one patient, irrespective of the different rewarming kinetics. Conclusions: T2 sympathectomy leads to long-lasting inhibition of palmar sweating, which does not correlate to loss of vasoconstriction. Recurrent and enhanced vasoconstrictor function 3 months following endoscopic sympathetic block has major implications for its use to treat enhanced vasoconstriction.

Catecholamine release in human skin: a microdialysis study

Dermal microdialysis might be a promising tool to investigate properties of sympathetic neurons in the skin as investigation of peripheral noradrenergic neurons in humans usually relies on highly variable vasoconstrictor reflexes or on indirect measurements like skin temperature recordings. To evaluate this technique, 21 experiments were performed in 15 healthy subjects with four intracutaneous microdialysis fibers (diameter, 200 microm; cutoff, 5 kDa) at hands or feet. After 60 min, saline perfusion tyramine at concentrations of 0.195 to 200 microg/ml was applied for 15 min followed by a 15-min saline perfusion again. Catecholamine concentrations were detected through high-performance liquid chromatography with electrochemical detection. Control experiments were performed in human skin homogenates with and without tyramine incubation. In vivo, norepinephrine (NE) concentration increased from 36.3 +/- 10.2 pg/ml to 84.4 +/- 18.4 pg/ml (P < 0.001) during stimulation with tyramine, dialysate dopamine (DA) concentration increased from 105.2 +/- 36.5 pg/ml to 7162.4 +/- 3972.4 pg/ml (P < 0.001). Both tyramine-induced NE and DA release were dose-dependent (NE: r = 0.438, P < 0.05; DA: r = 0.894, P < 0.001). In skin homogenates, tyramine incubation led to a significant increase of DA concentrations (387.0 +/- 34.8 pg/ml, controls: 13.2 +/- 2.4 pg/ml; P < 0.05), while NE and epinephrine levels remained unchanged. In conclusion, our experiments show that dermal microdialysis is capable of locally measuring catecholamines in human skin. This offers the opportunity to investigate the function of the peripheral sympathetic nervous system. Additional to non-enzymatic oxidation, DA increase probably reflects metabolic degradation of tyramine by non-neuronal pathways and therefore does not reflect local sympathetic innervation.

A System for Real-Time Endoscopic Image Enhancement

During endoscopic operations the surgeon works without direct visual contact to the operation area. The image of the operation situs is displayed on a monitor. Currently, only hardware based image enhancement methods are used (e. g., white balance) and often only once at the beginning of an operation. In this contribution we describe a system for real-time endoscopic image enhancement: a typical video-endoscopic system was extended by a computer and a second monitor. Thus the enhanced and the original image can be displayed at the same time. The implemented image enhancement methods (temporal filtering, undistortion and color normalization) were evaluated by 14 surgeons and the results showed that the enhanced images were preferred. The system was already used during a real operation.

Sequelae of endoscopic sympathetic block

Abstract.Endoscopic sympathetic block as a treatment for primary hyperhidrosis is associated with certain sequelae. The reported occurrence of side effects still varies in the literature. As the majority of patients describe sequelae after sympathetic surgery, the frequency and importance of these persisting changes are still underestimated. Patient’s informed consent should include and define side effects like gustatory sweating, olfactory sweating and bradycardia as likely, and compensatory sweating as obligatory.

Bildverarbeitung in der Endoskopie des Bauchraums

Derzeit werden bei endoskopischen Operationen, unter der Verwendung von Spezialfarbkameras, die unverarbeiteten Bilder aus dem Korper direkt auf einem Fernsehbildschirm dargestellt. Diese „direkte“ Darstellung der Bilder auf dem Fernsehbildschirm ist mit Einschrankungen der Darstellungsqualitat verbunden. Vor allem Glanzlichter, Verzerrungen, Farbfehler und Schwebepartikel beeintrachtigen die Bildqualitat. Es werden verschiedene Verfahren zur Verbesserung der Bildqualitat vorgestellt und evaluiert.

Differential effects of surgical sympathetic block at the T2 and T4 level on vasoconstrictor function.

Abstract.Endoscopic sympathetic block (ESB) is used as a treatment of excessive palmar sweating. In a prospective study we compared the effect of ESB at the level of the second (T2) and fourth thoracic ganglion (T4) on vasoconstriction and sweating of the hands. Sympathetic vasoconstriction was measured by computerassisted infrared thermography following ice water immersion of the hands in 22 hyperhidrosis patients before, two days and 3 months post op. In addition, palmar sweating before and 3 months post op was assessed by sudometry. After ESB the rewarming was accelerated in both T2 and T4 patients, but was significantly slower in the T4 group. Three months postoperatively rewarming had returned to the preoperative pattern in T4 patients but was still significantly faster in the T2 group. These effects were more pronounced in the fingertips than the hand dorsum. Sudomotor function was blocked in all T2 patients but had relapsed in 2 patients in the T4 group. Two T4 patients had not shown an effect on sudomotor function postoperatively. The normalization of rewarming kinetics may be explained by remaining fibers, denervation hypersensitivity or stimulation of catecholamine receptors, or neuronal reorganization. The effect of ESB T4 on sudomotor function has to be proven.