A Reduction of Calcineurin Inhibitors May Improve Survival in Patients with De Novo Colorectal Cancer after Liver Transplantation.

Background and Objectives: After liver transplantation (LT), long-term immunosuppression (IS) is essential. IS is associated with de novo malignancies, and the incidence of colorectal cancer (CRC) is increased in LT patients. We assessed course of disease in patients with de novo CRC after LT with focus of IS and impact on survival in a retrospective, single-center study. Materials and Methods: All patients diagnosed with CRC after LT between 1988 and 2019 were included. The management of IS regimen following diagnosis and the oncological treatment approach were analyzed: Kaplan−Meier analysis as well as univariate and multivariate analysis were performed. Results: A total of 33 out of 2744 patients were diagnosed with CRC after LT. Two groups were identified: patients with restrictive IS management undergoing dose reduction (RIM group, n = 20) and those with unaltered regimen (maintenance group, n = 13). The groups did not differ in clinical and oncological characteristics. Statistically significant improved survival was found in Kaplan−Meier analysis for patients in the RIM group with 83.46 (8.4−193.1) months in RIM and 24.8 (0.5−298.9) months in the maintenance group (log rank = 0.02) and showed a trend in multivariate cox regression (p = 0.054, HR = 14.3, CI = 0.96−213.67). Conclusions: Immunosuppressive therapy should be reduced further in patients suffering from CRC after LT in an individualized manner to enable optimal oncological therapy and enable improved survival.

FIRE-9 - PORT / AIO-KRK-0418: a prospective, randomized, open, multicenter Phase III trial to investigate the efficacy of adjuvant/additive chemotherapy in patients with definitely-treated metastatic colorectal cancer.

BACKGROUND: Additive/adjuvant chemotherapy as concept after local treatment of colorectal metastases has not been proven to be successful by phase III trials. Accordingly, a standard of care to improve relapse rates and long-term survival is not established and adjuvant chemotherapy cannot be recommended as a standard therapy due to limited evidence in literature. The PORT trial aims to generate evidence that post-resection/ablation/radiation chemotherapy improves the survival in patients with metastatic colorectal cancer. METHODS: Patients to be included into this trial must have synchronous or metachronous metastases of colorectal cancer-either resected (R0 or R1) and/or effectively treated by ablation or radiation within 3-10 weeks before randomization-and have the primary tumor resected, without radiographic evidence of active metastatic disease at study entry. The primary endpoint of the trial is progression-free survival after 24 months, secondary endpoints include overall survival, safety, quality of life, treatments (including efficacy) beyond study participation, translational endpoints, and others. One arm of the study comprising 2/3 of the population will be treated for 6 months with modified FOLFOXIRI or modified FOLFOX6 (investigator´s choice, depending on the performance status of the patients but determined before randomization), while the other arm (1/3 of the population) will be observed and undergo scheduled follow-up computed tomography scans according to the interventional arm. DISCUSSION: Optimal oncological management after removal of colorectal metastases is unclear. The PORT trial aims to generate evidence that additive/adjuvant chemotherapy after definitive treatment of colorectal metastases improves progression free and overall survival in patients with colorectal cancer. TRIAL REGISTRATION: This study is registered with clinicaltrials.gov ( NCT05008809 ) and EudraCT (2020-006,144-18).

Complete Pathological Response After Neoadjuvant Short-Course Immunotherapy with Ipilimumab and Nivolumab in Locally Advanced MSI-H/dMMR Rectal Cancer.

BACKGROUND: Patients with colorectal carcinoma and high-grade microsatellite instability (MSI-H) or deficiency in mismatch repair (dMMR) exceptionally respond to immune checkpoint inhibitors (ICIs). ICIs are more active in treatment-naïve patients than in patients with refractory MSI-H/dMMR metastatic colorectal cancer and even more active in patients with locally advanced tumors. MATERIAL AND METHODS: A 33-year-old male patient with Lynch syndrome was diagnosed with a locally advanced rectal cancer and refused standard neoadjuvant chemoradiation because of the potential harm of sexual dysfunction. MMR and microsatellite instability status were analyzed by immunohistochemistry and fragment length polymerase chain reaction followed by capillary electrophoresis. RESULTS: After MSI-H/dMMR was confirmed, the patient was treated with ICIs (1 mg/kg ipilimumab at day 1 and 3 mg/kg nivolumab at day 1 and 15). A complete clinical response was documented at day 21 after start of treatment. The patient underwent a total mesorectal excision at day 30. In the extirpated tissue, a complete pathological response was confirmed. CONCLUSION: In MSI-H/dMMR locally advanced rectal cancer short-course ICI treatment is highly effective and may be discussed in patients with dMMR locally advanced rectal cancer. KEY POINTS: Immune checkpoint inhibitors are more active in treatment-naïve patients than in patients with refractory high-grade microsatellite instability (MSI-H)/deficiency in mismatch repair (dMMR) colorectal cancer. Standard neoadjuvant chemoradiation is less effective in MSI-H/dMMR rectal cancer patients than in patients with proficient mismatch repair. A young patient with Lynch syndrome and MSI-H/dMMR locally advanced rectal cancer refused chemoradiation in order to preserve his fertility. After neoadjuvant treatment with one dose of ipilimumab and two doses of nivolumab a complete clinical and pathological response was documented. Clinical trials are needed to first establish neoadjuvant treatment with immune checkpoint inhibitors in patients with locally advanced MSI-H/dMMR rectal cancer and thereafter to evaluate organ-preservation strategies.

Initial Experience with the Safe Implementation of Transanal Total Mesorectal Excision (TaTME) as a Standardized Procedure for Low Rectal Cancer.

INTRODUCTION: The laparoscopic approach for TME is proven to be non-inferior in oncological outcome compared to open surgery. Anatomical limitations in the male and obese pelvis with resulting pathological shortcomings and high conversion rates were stimuli for alternative approaches. The transanal approach for TME (TaTME) was introduced to overcome these limitations. The aim of this study was to evaluate the outcomes of TaTME for mid and low rectal cancer at our center. METHODS: TaTME is a hybrid procedure of simultaneously laparoscopic and transanal mesorectal excision. A retrospective analysis of all consecutive TaTME procedures performed at our center for mid and low rectal cancer between December 2014 and January 2020 was conducted. RESULTS: A total of 157 patients underwent TaTME, with 72.6% receiving neoadjuvant chemoradiation. Mean tumor height was 6.1 ± 2.3 cm from the anal verge, 72.6% of patients had undergone neoadjuvant chemoradiotherapy, and 34.2% of patients presented with a threatened CRM upon pretherapeutic MRI. Abdominal conversion rate was 5.7% with no conversion for the transanal dissection. Early anastomotic leakage occurred in 7.0% of the patients. Mesorectum specimen was complete in 87.3%, R1 resection rate was 4.5% (involved distal resection margin) and in 7.6%, the CRM was positive. The three-year local recurrence rate of 58 patients with a follow-up ≥ 36 months was 3.4%. Overall survival was 92.0% after 12 months, and 82.2% after 36 months. CONCLUSION: TaTME can be performed safely with acceptable long-term oncological outcome. Low rectal cancer can be well addressed by TaTME, which is an appropriate alternative with low conversion, local recurrence, adequate mesorectal quality and CRM positivity rates.

Assessment of celiac artery compression using color-coded duplex sonography.

BACKGROUND: Median arcuate ligament syndrome (MALS) is a rare condition due to compression of the celiac artery (CA) by an anatomically abnormal median arcuate ligament. With ultrasonography (US) as first-line diagnostic modality in patients with unclear abdominal pain, there is limited data on its diagnostic performance in MALS. OBJECTIVE: To investigate the value of CA peak systolic velocity (PSV) in the workup of patients with suspected MALS. METHODS: Patients with diagnosis of MALS between 2009 and 2019 were referred by Department of Visceral Surgery after clinical and gastroenterological workup. Diagnosis was confirmed by surgery or further cross-sectional imaging. B-mode US findings and PSV in the CA during various respiratory states were compared between patients with a final MALS diagnosis and patients not meeting the diagnostic criteria. RESULTS: Patients with proven MALS (n = 10) had higher median CA PSV during normal inspiratory breath-hold (239 [IQR, 159-327] vs. 138 [IQR, 116-152] cm/s; p < #x003C;< #x200A;0.001), and expiratory breath-hold (287 [IQR, 191-412] vs. 133 [IQR, 115-194] cm/s; p < #x003C;< #x200A;0.001) compared to patients without MALS (n = 26). CA PSV in both inspiratory breath-hold (AUC 0.88, 95% CI 0.77-1.00) and expiratory breath-hold (AUC 0.89, 95% CI 0.78-1.00) was of diagnostic value for confirming MALS. The best diagnostic performance (100% sensitivity, 80% specificity) was found for the combination of CA PSVexpiration + 2.4 · PSVinspiration > 550 cm/s . CONCLUSIONS: Since results on optimal cutoff values are inconsistent, a combination of CA PSVs during breathing maneuvers may help to diagnose or rule out MALS.

Quantity-guided drain management reduces seroma formation and wound infections after radical lymph node dissection: results of a comparative observational study of 374 melanoma patients.

BACKGROUND: Lymphatic fistulas are common complications after lymph node dissections in melanoma patients. We investigated whether drain management could improve the patient's outcome. METHODS: Patients who underwent axillary or inguinal lymph node dissection (RALND or RILND) for malignant melanoma were recorded in a prospective database. Two different methods of drain management were compared. Either the drain was removed no later than the eighth postoperative day (period I, 2003-2007) or it was left in place until fluid flow was below 50 ml in 24 h for two consecutive days (period II, 2008-2011). The main outcome criterion was the incidence of seroma punctures after drain removal. RESULTS: 374 patients were analysed. The incidence of seroma punctures significantly decreased in period II. The number of patients with elevated lymphatic secretions rose by 41.3% (RALND) and 38.1% (RILND). With the exception of lymphatic fistulas, we observed significantly more local complications with need for treatment in period I (n = 104, 52%) than in period II (n = 31, 18%). In period II, the hospital stays after both procedures were significantly reduced. CONCLUSIONS: We conclude that quantity-guided drain management leads to a prolonged interval of drainage but is associated with a lower incidence of seroma formation and shorter hospital stay.

Poorly Differentiated Medullary Phenotype Predicts Poor Survival in Early Lymph Node-Negative Gastro-Esophageal Adenocarcinomas.

BACKGROUND: 5-year survival rate in patients with early adenocarcinoma of the gastro-esophageal junction or stomach (AGE/S) in Caucasian patients is reported to be 60-80%. We aimed to identify prognostic markers for patients with UICC-I without lymph-node involvement (N0). METHODS: Clinical data and tissue specimen from patients with AGE/S stage UICC-I-N0, treated by surgery only, were collected retrospectively. Tumor size, lymphatic vessel or vein invasion, grading, classification systems (WHO, Lauren, Ming), expression of BAX, BCL-2, CDX2, Cyclin E, E-cadherin, Ki-67, TP53, TP21, SHH, Survivin, HIF1A, TROP2 and mismatch repair deficiency were analyzed using tissue microarrays and correlated with overall and tumor related survival. RESULTS: 129 patients (48 female) with a mean follow-up of 129.1 months were identified. 5-year overall survival was 83.9%, 5-year tumor related survival was 95.1%. Poorly differentiated medullary cancer subtypes (p<0.001) and positive vein invasion (p<0.001) were identified as risk factors for decreased overall-and tumor related survival. Ki-67 (p = 0.012) and TP53 mutation (p = 0.044) were the only immunohistochemical markers associated with worse overall survival but did not reach significance for decreased tumor related survival. CONCLUSION: In the presented study patients with AGE/S in stage UICC-I-N0 had a better prognosis as previously reported for Caucasian patients. Poorly differentiated medullary subtype was associated with reduced survival and should be considered when studying prognosis in these patients.

Effects of psychological interventions and patients' affect on short-term quality of life in patients undergoing colorectal surgery.

Psychological interventions can improve Quality of Life (QoL). Object of interest was if different psychological interventions influence short-term QoL after colonic resection for carcinoma. Furthermore, we wanted to see if there is a correlation between patients` preoperative affect and postoperative QoL. Sixty patients that underwent colorectal surgery were divided into three groups. Group one (n = 20) received Guided Imagery and group 2 (n = 22) Progressive Muscle Relaxation. The third group (Control, n = 18) had no intervention. Quality of Life (QoL) was measured using the EORTC QLQ-C30 and the Gastrointestinal Quality of life Index (GIQLI). Patients' affect was measured by the PANAS questionnaire. The higher the preoperative Negative Affect was, the lower were the scores for QoL on the 30th postoperative day. Patients' QoL was highest preoperatively and lowest on the third postoperative day. On the 30th postoperative day scores for QoL were almost as high as preoperative without difference between the three groups. Neither Guided Imagery nor Progressive Relaxation was influencing short-term QoL measured by the EORTC QLQ-C30 and the GIQLI questionnaire after colorectal surgery for cancer. Screening patients' with the PANAS questionnaire might help to identify individuals that are more likely to have a worse QoL postoperatively.

Regional nodal relapse in surgically staged Merkel cell carcinoma.

PURPOSE: The nodal relapse pattern of surgically staged Merkel cell carcinoma (MCC) with/without elective nodal radiotherapy (RT) was studied in a single institution. METHOD: A total of 51 patients with MCC, 33% UICC stage I, 14% II, 53% III (4 lymph node metastases of unknown primary) were eligible. All patients had surgical staging: 23 patients sentinel node biopsy (SNB), 22 patients SNB followed by lymphadenectomy (LAD) and 6 patients LAD. In all, 94% of the primary tumors (PT) were completely resected; 57% of patients received RT, 51% of known PT sites, 33% (8/24 patients) regional RT to snN0 nodes and 68% (17/27 patients) to pN+ nodes, mean reference dose 51.5 and 50 Gy, respectively. Mean follow-up was 6 years (range 2-14 years). RESULTS: A total of 22% (11/51) patients developed regional relapses (RR); the 5-year RR rate was 27%. In snN0 sites (stage I/II), relapse occurred in 5 of 14 nonirradiated vs. none of 8 irradiated sites (p = 0.054), resulting in a 5-year RR rate of 33% versus 0% (p = 0.16). The crude RR rate was lower in stage I (12%, 2/17 patients) than for stage II (43%, 3/7 patients). In stage III (pN+), RR appeared to be less frequent in irradiated sites (18%, 3/14 patients) compared with nonirradiated sites (33%, 3/10 patients, p = 0.45) with 5-year RR rates of 23% vs. 34%, respectively. DISCUSSION: Our data suggest that adjuvant nodal RT plays a major role even if the sentinel nodes were negative. CONCLUSION: Adjuvant RT of the lymph nodes in patients with stage IIa tumors and RT after LAD in stage III tumors is proposed and should be evaluated prospectively.

Vagus-preserving technique during minimally invasive esophagectomy: the effects on cardiac parameters in a swine model.

BACKGROUND: Cardiac complications are an important cause of morbidity and mortality observed after esophageal resections. We examined whether an high intrathoracic vagotomy during abdominothoracic esophagectomy would have an effect on intraoperative and early postoperative cardiac function in the setting of a minimally invasive resection. Two hypotheses were generated for this study: (1) Vagotomy would cause cardiac changes, and (2) vagus-preserving esophagectomy would prevent cardiac problems during resection and in the early postoperative phase. METHODS AND RESULTS: Thirty male pigs were operated on while cardiac parameters (heart rate [HR], cardiac index [CI], preload recruitable stroke work [PRSW], contractility speed [dp/dtmax], relaxation speed [dp/dtmin], and relaxation time [tau]) were monitored using a conductance catheter and the thermodilution method. Animals were randomized into 4 groups (each n = 7): (1) control, thoracoscopy only, (2) thoracoscopy with vagotomy, (3) esophageal resection with vagotomy, and (4) esophageal resection with vagus nerve preservation. To evaluate the first hypothesis, we compared groups 1 and 2; to evaluate the second hypothesis, we compared groups 3 and 4. HR, CI, PRSW, dp/dtmax, and tau were different in the 2 groups without resection (area under the curve; each P < .05). Vagotomy with esophagectomy resulted in nonsignificant differences between groups 3 and 4. The requirement for metoprolol administration to avoid severe tachycardia was greater in the groups that underwent vagotomy (P < .05; Fisher's exact test). CONCLUSION: An high intrathoracic vagotomy results in loss of vagal tone and a greater rate of tachycardia during thoracoscopy and esophagectomy. There were no differences, however, in cardiac dynamics between the esophagectomy groups. Thus, vagal injury is not the sole reason for cardiac dysfunction after esophagectomy.

Continuous local analgesic therapy reduces pain after radical inguinal/iliacal lymph node dissection.

BACKGROUND: To optimize postoperative pain therapy after a radical inguinal/iliacal lymph node dissection (RILND), we investigated the influence of a continuous application of a local anaesthetic via a subfascial wound catheter in the abdominal wall in addition to a standardized systemic analgesia. MATERIALS AND METHODS: Between July 2007 and December 2009, 50 patients with stage III/IV of melanoma disease received, in an observational study, a systemic analgesic therapy. Of these patients, 30 were additionally treated with a subfascial catheter. Main outcome criterion was the pain under mobilisation at the first postoperative morning registered via a visual analogue score. Minor criteria were the analgesic requirement, the specific (surgical) complications and the day of discharge. RESULTS: Patients treated with the subfascial catheter had significant less pain at the first postoperative morning in rest (p = 0.02) and after mobilisation (p = 0.03) without increased morbidity (p = 0.45). Less patients of the treatment group needed a supplementary analgesic medication (p = 0.01) and were able to leave hospital earlier than patients of the control group (p = 0.01). CONCLUSIONS: A subfascially placed pain catheter enhances postoperative pain therapy after RILND.

Preemptive analgesia reduces pain after radical axillary lymph node dissection.

BACKGROUND: Analyzing prospective data of our melanoma patients, we registered a suboptimal pain score under mobilization after radical axillary lymph node dissection (RALND). We performed a randomized, double blinded clinical trial to investigate the effects of a preemptive Parecoxib analgesic during the perioperative course. MATERIALS AND METHODS: Between October 2006 and December 2007, 32 patients with stage III/IV melanoma underwent therapeutic RALND and were randomized into two groups. Patients received intravenously 40 mg Parecoxib or 0.9% normal saline solution 2 h before RALND. The postoperative treatment and analgetic regime was defined in the study protocol. Main outcome criterion was the pain under mobilization at the first postoperative morning registered via a visual analogue score. Minor criteria were the postoperative complications, fatigue, amount of analgesics, and the day of discharge. RESULTS: Patients receiving a preemptive analgesic had a better outcome after RALND. The pain after mobilization was significantly decreased at the first postoperative morning (P = 0.04). Patients had less fatigue as well (P = 0.05) and the amount of pain medication in the treatment group was reduced (P = 0.04). CONCLUSIONS: Preemptive application of Parecoxib enhances outcome after RALND. A preemptive analgesic with Parecoxib in the perioperative management after RALND of melanoma patients can be recommended.

Acute partial segmental thrombosis of the corpus cavernosum: imaging findings on ultrasound, computed tomography, and magnetic resonance imaging.

Partial segmental thrombosis of the corpus cavernosum is a rare disease of unknown etiology; the thrombosis is always located in the proximal part of the corpus cavernosum, usually unilaterally. Typical clinical presentation with perineal pain and swelling in combination with cross-sectional imaging allows one to confidentially establish this diagnosis.

Stress and heart rate variability in surgeons during a 24-hour shift.

OBJECTIVE: To determine the specific effects of working long hours in surgery and potential cardiac stress in the individual surgeon by measuring heart rate variability (HRV). DESIGN, SETTING, AND PARTICIPANTS: This prospective study measured HRV before, during, and after a 24-hour shift in a standardized resting period of 10 minutes. Measurements were repeated over 10 shifts for each participant. Eight surgeons from a high-volume inner-city surgery department took part in the study. MAIN OUTCOME MEASURES: Time and frequency domain parameters of HRV as parameters of cardiac stress and correlations with perceived stress and fatigue on a visual analog scale. RESULTS: Perceived fatigue increased over 24 hours (P < .001), whereas stress levels decreased slightly (P = .06). Time domain parameters of HRV increased from before the shift to after the shift (standard deviation of normal to normal intervals, square root of the mean normal to normal interval, and percentage of adjacent pairs of normal to normal intervals differing by more than 50 milliseconds: all P < .01), denoting more cardiac relaxation. Both the low- and high-frequency components increased (P = .04 and P < .001, respectively), showing a heightened activity of the autonomic nervous system. CONCLUSIONS: Measurements of HRV during a 24-hour surgical shift did not show an increase in cardiac stress concerning time domain parameters despite intense workloads for a median of 20 hours. Frequency components increased in parallel, though, suggesting alterations in sympathovagal balance. Perceived stress levels correlated with HRV, whereas fatigue did not. Further studies on occupational stress and its cardiac effects in surgeons are needed.

Methodological quality of randomised controlled trials comparing short-term results of laparoscopic and conventional colorectal resection.

BACKGROUND: Randomised, controlled trials (RCT) and systematic reviews of RCT with meta-analysis are considered to be of highest methodological quality and therefore are given the highest level of evidence (Ia/b). Although, "low-quality" RCT may be downgraded to level of evidence IIb, the methodological quality of each individual RCT is not respected in detail in this classification of the level of evidence. MATERIALS AND METHODS: Within a systematic Cochrane Review of RCT on short-term benefits of laparoscopic or conventional colorectal resections, the methodological quality of all included RCT was evaluated. All RCT were assessed by the Evans and Pollock questionnaire (E and P increasing quality from 0-100) and the Jadad score (increasing quality from 0-5). RESULTS: Publications from 28 RCT printed from 1996 to 2005 were included in the analysis. Methodological quality of RCT was only moderate [E & P 55 (32-84); Jadad 2 (1-5)]. There was a significant correlation between the E & P and the Jadad score (r = 0.788; p < 0.001). Methodological quality of RCT slightly increased with increasing number of patients included (r = 0.494; p = 0.009) and year of publication (r = 0.427; p = 0.03). Meta-analysis of all RCT yielded clinically relevant differences for overall and local morbidity when compared to meta-analysis of "high-quality" (E & P > 70) RCT only. CONCLUSION: The methodological quality of reports of RCT comparing laparoscopic and open colorectal resection varies considerably. In a systematic review, methodological quality of RCT should be assessed because meta-analysis of "high-quality" RCT may yield different results than meta-analysis of all RCT.

Hypovolemia after traditional preoperative care in patients undergoing colonic surgery is underrepresented in conventional hemodynamic monitoring.

BACKGROUND AND AIMS: Hypovolemia after bowel preparation as well as capnoperitoneum (CP) may compromise hemodynamic function during laparoscopic colonic surgery. A fall in arterial pressure after induction of anesthesia is often answered by generous fluid administration, which might impair "fast-track" rehabilitation. Intraoperative assessment of the needed infusion volume is difficult because of a lack of data regarding the volume status in these patients. PATIENTS AND METHODS: Nineteen patients scheduled for laparoscopic colonic surgery after bowel preparation were prospectively monitored using the PULSION COLD Z-021 system and central venous catheter. Intrathoracic blood volume index (ITBVI), mean arterial pressure (MAP), cardiac index (CI), central venous pressure (CVP), and heart rate (HR) were measured after induction of anesthesia (M1), during CP in head-down position with an intraabdominal pressure (IAP) of 20 mmHg (M2) and 12 mmHg (M3). RESULTS: Although MAP (87 mmHg), HR (64 min(-1)), and CVP (8 mmHg) were within normal ranges at the induction of surgery, ITBVI (834 ml m(-2)), and CI (2.66 l m(-2)) were decreased, indicating a relative hypovolemia. CP with 12 mmHg increased ITBVI (p<0.05) and CI (p<0.01), while an IAP of 20 mmHg reduced CI (p<0.05) compared to 12 mmHg (M3). Mean infusion during the measurements was 1,355 ml. CONCLUSION: Combination of CP with 12 mmHg, head-down position, and infusion of 1,500 ml fluids compensated relative hypovolemia during colonic surgery. With conventional monitoring, intravascular volume status might be underestimated after traditional preoperative care.

Effect of increasing cardiac preload, sympathetic antagonism, or vasodilation on visceral blood flow during pneumoperitoneum.

BACKGROUND AND AIMS: An impaired visceral perfusion caused by pneumoperitoneum may contribute to morbidity after laparoscopic surgery. The following three therapeutic concepts: increasing cardiac preload, controlled vasodilation, or selective sympathetic antagonism, were evaluated regarding a possible increase of visceral blood flow during pneumoperitoneum with carbon dioxide. METHODS: Forty three pigs were assigned to treatment with an increase of preload and vasodilation (group A) or selective sympathetic antagonism with esmolol (group B). In both groups, pigs were assigned to head-up, head-down, or supine position. Perfusion of the vena porta and renal artery was measured by transonic volume flow meters and documented before capnoperitoneum, after induction of a 14-mmHg capnoperitoneum in each body position, after controlled vasodilation with sodium nitroprusside, and after controlled increase of intravascular volume by colloidal infusion. RESULTS: Increasing intravascular volume improved portal blood flow in all body positions (p<0.05), but not renal blood flow. Medication of esmolol did not alter the measured parameters in any body position compared to control. Vasodilation with sodium nitroprusside reduced renal blood flow in supine and in head-up position. CONCLUSION: An optimal intravascular volume was most effective in improving portal blood flow during capnoperitoneum in this trial. Esmolol had no negative effects on portal and renal blood flow. Patients with renal dysfunction might be treated carefully with sodium nitroprusside during capnoperitoneum.

Induction and repair of radiation-induced DNA double-strand breaks in human fibroblasts are not affected by terminal differentiation.

It was studied for human skin fibroblasts, whether the induction or repair of DNA double-strand breaks (dsb) depend on the differentiation status. These studies were performed (a) with a fibroblast strain (HSF1) kept in progenitor state (mitotic fibroblasts, MF) or triggered to premature terminal differentiation (postmitotic fibrocytes, PMF) by exposure to mitomycin C or (b) with 20 fibroblast strains differing intrinsically in their differentiation status. The differentiation status was quantified by determining the fraction of postmitotic fibrocytes by light microscopy. DNA dsb were measured by constant-field gel electrophoresis, and the fraction of apoptotic cells by comet assay. MF and PMF cultures of HSF1 cells were irradiated with X-ray doses up to 160 Gy, and dsb were measured either immediately after irradiation or after a repair incubation of 4 or 24 h. There were a difference neither in the number of initial nor residual dsb. PMF cultures, however, showed a slightly higher number of dsb already present in non-irradiated cells, which was measured to result from a small fraction of 5% apoptotic cells. The 20 analysed fibroblast strains showed a substantial variation in the fraction of postmitotic fibrocytes (9-51%) as well as in the number of dsb remaining at 24 h after irradiation (1.9-4.9%), but there was no correlation between these two parameters. These data demonstrate that for fibroblasts the terminal differentiation has an effect neither on the induction nor the repair of radiation-induced dsb. This result indicates that the variation in dsb-repair capacity previously observed for fibroblast strains and which was considered to be the main cause for the variation in the cellular radiosensitivity, cannot be ascribed to differences in the differentiation status.

Fibrosis and cytokine mechanisms: relevant in hadron therapy?

BACKGROUND: Cytokines are important for signalling between cells and tissues and constitute a humoral component of the response of cells and tissues to radiotherapy. Although several cytokines have been implicated in mediating radiation-induced reactions of normal tissues to both conventional photon and heavy ion irradiation, the mechanisms are only beginning to be elucidated. MATERIAL AND METHODS: Published and own data on radiation-induced cytokine expression from cell culture and clinical studies are reviewed. Current models of cytokine-mediated multicellular interactions in radiation-induced reactions are presented. RESULTS AND CONCLUSION: The major cytokines in the radiation response of non-hemopoietic tissues include IL-6, IL-1, TNF-alpha and TGF-beta. Different cell types interact via cytokines in a complex network of effector and receptor cells, including inflammatory cells, tissue-specific functional cells and fibroblasts. TGF-beta appears to be of particular importance in the development of late reactions to radiation therapy, such as fibrosis, in response to both conventional therapy as well as hadron therapy.