Surgical treatment options following chemotherapy plus cetuximab or bevacizumab in metastatic colorectal cancer-central evaluation of FIRE-3.

BACKGROUND: The FIRE-3 trial investigated combination chemotherapy plus either cetuximab or bevacizumab in patients with untreated metastatic colorectal cancer (mCRC) not scheduled for upfront surgery. We aimed to determine the number of patients who present with potentially resectable disease during systemic first-line therapy and to compare the findings with study reports concerning resections and outcome. PATIENTS AND METHODS: This evaluation of 448 patients was performed as central review blinded for treatment, other reviewers' evaluations and conducted interventions. Resectability was defined if at least 50% of the reviewers recommended surgical-based intervention. Overall survival was assessed by Kaplan-Meier method. RESULTS: Resectability increased from 22% (97/448) at baseline before treatment to 53% (238/448) at best response (P < 0.001), compared with an actual secondary resection rate for metastases of 16% (72/448). At baseline (23% versus 20%) and best response (53% versus 53%), potential resectability of metastases in this molecular unselected population was similar in cetuximab-treated patients versus bevacizumab-treated patients and not limited to patients with one-organ disease. The actual resection rate of metastases was significantly associated with treatment setting (P = 0.02; university hospital versus hospital/practice). Overall survival was 51.3 months (95% confidence interval [CI] 35.9-66.7) in patients with resectable disease who received surgery, 30.8 months (95% CI 26.6-34.9) in patients with resectable disease without surgery and 18.6 months (95% CI 15.8-21.3) in patients with unresectable disease (P < 0.001). CONCLUSIONS: Our findings illustrate the potential for conversion to resectability in mCRC, certain reluctance towards metastatic resections in clinical practice and the need for pre-planned and continuous evaluation for metastatic resection in high-volume centres. CLINICALTRIALS. GOV-IDENTIFIER: NCT00433927.

Moon phases and moon signs do not influence morbidity, mortality and long-term survival, after living donor kidney transplantation.

BACKGROUND: Approximately 11% of the German population are convinced that certain moon phases and moon signs may impact their health and the onset and clinical course of diseases. Before elective surgery, a considerable number of patients look to optimize the timing of the procedure based on the lunar cycle. Especially patients awaiting living donor kidney transplantation (LDKT) commonly look for an adjustment of the date of transplantation according to the moon calendar. This study therefore investigated the perioperative and long-term outcome of LDKT dependent on moon phases and zodiac signs. METHODS: Patient data were prospectively collected in a continuously updated kidney transplant database. Two hundred and seventy-eight consecutive patients who underwent LDKT between 1994 and December 2009 were selected for the study and retrospectively assigned to the four moon phases (new-moon, waxing-moon, full-moon, and waning-moon) and the corresponding zodiac sign (moon sign Libra), based on the date of transplantation. Preexisting comorbidities, perioperative mortality, surgical outcome, and long-term survival data were analyzed. RESULTS: Of all LDKT procedures, 11.9, 39.9, 11.5, and 36.5% were performed during the new, waxing, full, and waning moon, respectively, and 6.2% during the moon sign Libra, which is believed to interfere with renal surgery. Survival rates at 1, 5, and 10 years after transplantation were 98.9, 92, and 88.7% (patient survival) and 97.4, 91.6, and 80.6% (graft survival) without any differences between all groups of lunar phases and moon signs. Overall perioperative complications and early graft loss occurred in 21.2 and 1.4%, without statistical difference (p > 0.05) between groups. CONCLUSION: Moon phases and the moon sign Libra had no impact on early and long-term outcome measures following LDKT in our study. Thus, concerns of patients awaiting LDKT regarding the ideal time of surgery can be allayed, and surgery may be scheduled independently of the lunar phases.

Spiegelmer Inhibition of MCP-1/CCR2--Potential as an Adjunct Immunosuppressive Therapy in Transplantation.

The rejection process remains the key unsolved issue after transplantation of disparate tissue. The CC chemokine monocyte chemoattractant protein-1 (MCP-1/CCL2) has been reported to be involved in the process of alloimmune interaction. Spiegelmers are l-oligonucleotides that can be designed to bind to pharmacologically relevant target molecules. Here, we tested a high-affinity Spiegelmer-based MCP-1 inhibitor (mNOX-E36) in an allogeneic heart transplant model. Fully vascularized allogeneic heterotopic heart transplantations from BALB/c to C57BL/6 mice were performed. Mice were either treated with the anti-MCP-1-Spiegelmer (mNOX-E36) in monotherapy or in combination with subtherapeutic doses of cyclosporine A (CsA) (10 mg/kgBW/day) for 10 days. Controls received equivalent doses of a non-functional Spiegelmer (revmNOX-E36). Graft survival of allogeneic heart transplants was slightly but significantly prolonged under mNOX-E36 monotherapy (median graft survival 10 day ± 0.7) compared to revmNOX-E36 (median graft survival 7 day ± 0.3; P = 0.001). A synergistic beneficial effect could be seen when mNOX-E36 was administered in combination with subtherapeutic doses of CsA (18 day ± 2.8 versus 7 day ± 0.3; P < 0.0001). Levels of inflammatory cytokines and 'alarmins' were significantly reduced, and the number of F4/80(+) cells was lower under combination therapy (1.8% ± 1.3%; versus 14.6% ± 4.4%; P = 0.0002). This novel inhibitor of the MCP-1/CCR2 axis (mNOX-E36), which has already proven efficacy and tolerability in early clinical trials, alleviates acute rejection processes in allogeneic transplantation especially when combined with subtherapeutic doses of CsA. Thus, mNOX-E36 may have potential as an adjunct immunomodulatory agent.

[Therapy of hepatocellular carcinoma before liver transplantation]. / Therapie des hepatozellulären Karzinoms vor Lebertransplantation.

Liver transplantation is the optimal therapy for patients with non-resectable early stage hepatocellular carcinoma (HCC) which is limited to the liver. During the sometimes long waiting period patients usually receive neoadjuvant bridging therapy to avoid tumor progression. The armamentarium of bridging therapies includes local ablative and systemic therapies as well as liver resection. The oncological benefit of neoadjuvant therapy for patients who receive a liver transplantation is unclear; however, bridging therapy keeps patients eligible for transplantation in the formal framework of current allocation rules. Moreover, response to therapy may serve as a surrogate marker for favorable tumor biology and may therefore help to guide the selection process for patients undergoing liver transplantation for HCC.

Influence of hepatitis C virus infection and high virus serum load on biliary complications in liver transplantation.

BACKGROUND: Biliary complications (BCs) and recurrent hepatitis C virus (HCV) infection are among the major causes of morbidity and graft loss following liver transplantation. The influence of HCV on BCs has not been definitely clarified. PATIENTS AND METHODS: We performed a retrospective cohort study to analyze risk factors and outcome of post orthotopic liver transplantation (OLT) BCs in 352 liver transplant recipients over 12 years in Munich, Germany (n = 84 with HCV; living donor and re-OLT were excluded). BCs diagnosed with imaging techniques and abnormal liver enzyme pattern, requiring an intervention, were considered. RESULTS: In a multivariate analysis, HCV serostatus and a high pre-and post-surgery HCV RNA serum load were independent risk factors for anastomotic strictures. HCV positivity and BCs alone did not alter graft loss. HCV-positive patients with BCs, however, had a significantly worse graft outcome (P = 0.02). Non-anastomotic strictures, bile leaks, and the number of interventions needed to treat bile leaks led to worse graft outcome in all patients. CONCLUSION: HCV positivity and a high HCV RNA serum load were risk factors for anastomotic strictures. BCs and HCV had an additive effect on graft loss.

Multimodality treatment for early-stage hepatocellular carcinoma: a bridging therapy for liver transplantation.

PURPOSE: To evaluate the efficiency of a multimodality approach consisting of transcatheter arterial chemoembolization (TACE) and radiofrequency ablation (RFA) as bridging therapy for patients with hepatocellular carcinoma (HCC) awaiting orthotopic liver transplantation (OLT) and to evaluate the histopathological response in explant specimens. MATERIALS AND METHODS: Between April 2001 and November 2011, 36 patients with 50 HCC nodules (1.4-5.0 cm, median 2.8 cm) on the waiting list for liver transplantation were treated by TACE and RFA. The drop-out rate during the follow-up period was recorded. The local efficacy was evaluated by histopathological examination of the explanted livers. RESULTS: During a median follow-up time of 29 (4.0-95.3) months the cumulative drop-out rate for the patients on the waiting list was 0, 2.8, 5.5, 11.0, 13.9 and 16.7% at 3, 6, 12, 24, 36 and 48 months, respectively. 16 patients (with 26 HCC lesions) out of 36 (44.4%) were transplanted by the end of study with a median waiting list time of 13.7 (2.5-37.8) months. The histopathological examination of the explanted specimens revealed a complete necrosis in 20 of 26 HCCs (76.9%), whereas 6 (23.1%) nodules showed viable residual tumor tissue. All transplanted patients are alive at a median time of 29.9 months. Imaging correlation showed 100% specificity and 66.7% sensitivity for the depiction of residual or recurrent tumor. CONCLUSION: We conclude that TACE combined with RFA could provide an effective treatment to decrease the drop-out rate from the OLT waiting list for HCC patients. Furthermore, this combination therapy results in high rates of complete tumor necrosis as evaluated in the histopathological analysis of the explanted livers. Further randomized trials are needed to demonstrate if there is a benefit in comparison with a single-treatment approach.

Multimodality treatment with conventional transcatheter arterial chemoembolization and radiofrequency ablation for unresectable hepatocellular carcinoma.

BACKGROUND/AIMS: To evaluate the efficacy of multimodality treatment consisting of conventional transcatheter arterial chemoembolization (TACE) and radiofrequency ablation (RFA) in patients with non-resectable and non-ablatable hepatocellular carcinoma (HCC). METHODS: In this retrospective study, 85 consecutive patients with HCC (59 solitary, 29 multifocal HCC) received TACE followed by RFA between 2001 and 2010. The mean number of tumors per patient was 1.6 ± 0.7 with a mean size of 3.0 ± 0.9 cm. Both local efficacy and patient survival were evaluated. RESULTS: Of 120 treated HCCs, 99 (82.5%) showed a complete response (CR), while in 21 HCCs (17.5%) a partial response was depicted. Patients with solitary HCC revealed CR in 91% (51/56); in patients with multifocal HCC (n = 29) CR was achieved in 75% (48 of 64 HCCs). The median survival for all patients was 25.5 months. The 1-, 2-, 3- and 5-year survival rates were 84.6, 58.7, 37.6 and 14.6%, respectively. Statistical analysis revealed a significant difference in survival between Barcelona Clinic Liver Cancer (BCLC) A (73.4 months) and B (50.3 months) patients, while analyses failed to show a difference for Child-Pugh score, Cancer of Liver Italian Program (CLIP) score and tumor distribution pattern. CONCLUSION: TACE combined with RFA provides an effective treatment approach with high local tumor control rates and promising survival data, especially for BCLC A patients. Randomized trials are needed to compare this multimodality approach with a single modality approach for early-stage HCC.

Endovascular versus open treatment of degenerative aneurysms of the descending thoracic aorta: a single center experience.

Multiple reports could show a reduced risk for thoracic endovascular aortic repair (TEVAR) compared with open treatment. The aim of this study was to evaluate our twelve-year TEVAR experience for thoracic aortic aneurysms and compare these results with open repair. All patients who had received either open or endovascular surgery for a degenerative aortic aneurysm of the descending thoracic aorta in our center were evaluated retrospectively. N = 53 TEVAR patients (1997-2008) were included and their course was compared with an open-surgery group of n = 24 patients (1992-2002). The percentage of symptomatic patients was 43% (TEVAR) and 42% (open surgery). Endovascular treatment resulted in a significantly reduced 30-day (5.7% versus 25% P = 0.02) and one-year mortality (19% versus 42% P = 0.05) in the entire cohort. Symptomatic patients benefited the most from TEVAR (30-day mortality: 9% versus 40%, P = 0.06; one-year mortality: 27% versus 70%, P = 0.049) whereas the survival of our asymptomatic patients was not significantly different (30-day mortality: 3% versus 14%, P = 0.22; one-year mortality: 13% versus 21%, P = 0.65). Lastly, Kaplan-Meier analysis showed a significantly improved survival after TEVAR (P = 0.05) and in particular for the symptomatic patients (P = 0.003). In conclusion, endovascular treatment for patients with degenerative thoracic aortic aneurysms has significant advantages over open surgery.

[Cyberknife surgery with a radio-scalpel: a new treatment option for patients with unresectable metastases]. / Cyberknife-Chirurgie mit dem Strahlenmesser: eine neue Behandlungsalternative für Patienten mit inoperablen Metastasen.

Patients with non-resectable metastases of various diseases are today treated by one of several different techniques, such as radiofrequency ablation, laser-induced thermoablation or stereotactic radiotherapy. Frequently, the employment of these therapeutic strategies is limited due to their invasiveness and treatment-associated morbidity. Furthermore, stereotactic radiotherapy is associated with a high degree of patient discomfort due to the necessary fixation of moving inner organs (lung, liver). With the development of the cyberknife radiosurgery technique, an image-guided, superselective, robot-based radiotherapy, these problems seem to be resolved. With this technique, metastases may be treated in an outpatient single-treatment setting.

Blumgart anastomosis for pancreaticojejunostomy minimizes severe complications after pancreatic head resection.

BACKGROUND: Leakage from the pancreaticojejunostomy is the major cause of septic complications after partial pancreaticoduodenectomy. This study evaluated a new transpancreatic U-suture technique (Blumgart anastomosis, BA), which aims to avoid shear forces during knot-tying. METHODS: Using a before-after study design, BA was compared with a modified Cattell-Warren anastomosis (CWA). Two patient cohorts (CWA, 90; BA, 92), which were similar with respect to primary diagnosis, age, sex and American Society of Anesthesiologists score, were compared retrospectively. Dependent variables were surgical and overall morbidity and mortality after partial pancreaticoduodenectomy. RESULTS: Duration of operation (354 versus 328 min for CWA versus BA; P = 0.002), pancreatic leakage rate (13 versus 4 per cent; P = 0.032), postoperative haemorrhage (11 versus 3 per cent; P = 0.040), total surgical complications (31 versus 15 per cent; P = 0.011), general complications (36 versus 17 per cent; P = 0.005) and length of intensive care unit stay (median 5.4 versus 2.8 days; P = 0.015) were significantly reduced after BA. These effects were not related merely to an improvement over time. CONCLUSION: BA appears to be a fast, simple and safe technique for pancreaticojejunostomy. It might reduce leakage rates and surgical complications after partial pancreaticoduodenectomy.

The janus face of immunosuppression - de novo malignancy after renal transplantation: the experience of the Transplantation Center Munich.

After decades of successful organ transplantation clinicians continue to be troubled by the increasing incidence of cancers under maintenance immunosuppression. In this study, we examined rates of malignancies in 2419 renal transplant recipients transplanted in our institution between 1978 and 2005. In renal transplant recipients the cumulative incidence of cancer after 25 years was 49.3% for all tumors and 39.7% excluding non-melanoma skin cancers, compared with 21% for a normal sex- and age-matched population. The most frequent tumors observed were non-melanoma skin cancers (20.5%), kidney cancers (12.0%), and cancers of the pharynx, larynx, or oral cavity (8.2%). The general increase of cancer risk was 4.3-fold. Independent risk factors for the development of a tumor were male gender, older recipient age, the presence of preformed antibodies before transplantation, and the time on immunosuppression. Interestingly, the use of IL-2-receptor antagonists significantly reduced the tumor risk of transplant recipients. The tumor risk between immunosuppressive drugs typically used for maintenance immunosuppression was not significantly different. However, mammalian target of rapamycin (mTOR) inhibitor-based immunosuppressive protocols showed a clear tendency for lower malignancy rates. De novo malignancies following renal transplantation represent a serious problem endangering the prognosis of otherwise successfully transplanted patients. Future studies will have to address whether optimized immunosuppressive regimens including mTOR-inhibitors are capable of reducing the incidence or preventing the development of posttransplant malignancies.

Laparoscopic mesh repair of incisional hernia: an alternative to the conventional open repair?

BACKGROUND: Tension-free incisional hernia repair using alloplastic material increasingly replaces conventional repair techniques. This change resulted in a decreased recurrence rate (50% vs. 10%, respectively). Recently, laparoscopic approaches for the intraperitoneal tension-free mesh application have been introduced. The decreased trauma at the incision site and the reduction in wound infections appear to be the main advantages. The aim of the present study was to evaluate the early and long-term complications as well as patients' contentment. METHODS: Laparoscopic hernia repair with intraperitoneal polytetrafluroethylene (PTFE) mesh implantation was performed on 62 patients at the Klinikum Grosshadern between 2000 and 2005 (29 males, 33 females age 60.7). Intra- and postoperative complications were registered prospectively and retrospectively analyzed. In addition, 57 patients were evaluated for recurrence, postoperative pain and patient contentment (median follow-up 409 days). RESULTS: A low complication rate was observed in our patient collective. One trocar bleeding occurred. Three patients presented with wound hematoma. The recurrence rate was 8% (2/25). Sixty-two percent of the patients were free of complaints postoperatively. Eighty-five percent would once again choose the laparoscopic approach for incisional hernia repair. CONCLUSION: The laparoscopic technique was associated with a low recurrence rate, a small rate of wound infections and high patient comfort. Thus, the laparoscopic approach for mesh implantation appears to be a safe and effective method for the treatment of incisional hernias. The efficiency for laparoscopic intraperitoneal mesh implantation, however, should be further evaluated within a prospectively randomized multicenter trial.

[Titanium-coated silicone is not effective for preventing graft infection]. / Die Beschichtung von Silikonimplantaten mit Titan ist nicht effektiv zur Vermeidung von Infektionen.

AIM: Titanium-coated grafts for breast augmentation are available since 2001 and are used clinically. The titan surface is supposed to improve the tissue compatibility and to lower the infection rate. It was the aim of the present study to validate the antibacterial efficiency of titanium-coated silicone. MATERIAL AND METHODS: C3H/HcN mice were assigned to four different groups (n=6/group). Silicone without (group I and III) or with (group II and IV) titanium were implanted subcutaneously. Following this in groups III and IV a local contamination was induced with 2 x 10 (7) CFU/0.1 ml Staphylococcus aureus ATCC 25923. Groups I and II were not infected. 14 days after primary operation all animals were euthanized and the grafts harvested. Specimens were examined for signs of infections by macroscopy, histology and microbiology. RESULTS: In group I none of the grafts were infected (0/5). In group II (silicone, + titanium, no contamination) one infection was evident due to biting of the animal (1/6). In group III (silicone, no titanium, contamination) an infection was detected in all mice (6/6). The use of titanium, however, did not significantly reduce the infection rate in contaminated animals (group IV, 5/6). Interestingly, tissue integration of titanium-coated grafts was macroscopically reduced compared to non- titanium-coated grafts (group II vs. I). CONCLUSION: The titanium-coated silicone grafts were not effective in protecting infection in vivo. The decreased tissue integration of titanium-coated grafts, however, might reduce the rate of capsular contracture. This potential advantage of titanium needs to be validated in controlled clinical trials.

Survival benefit in patients after palliative resection vs non-resection colon cancer surgery.

AIM: To evaluate survival in patients undergoing palliative resection versus non-resection surgery for primary colorectal cancer in a retrospective analysis. METHODS: Demographics, TNM status, operating details and survival were reviewed for 67 patients undergoing surgery for incurable colorectal cancer. Palliative resection of the primary tumor was performed in 46 cases in contrast to 21 patients with non-resection of the primary tumor and bypass surgery. Risk factors for postoperative mortality and poor survival were analyzed with univariate and multivariate analyses. RESULTS: The two groups were comparable in terms of age, gender, preoperative presence of ileus and tumor stage. Multivariate analysis showed that median survival was significantly higher in patients with palliative resection surgery (544 vs 233 d). Differentiation of the tumor and tumor size were additional independent factors that were associated with a significantly poorer survival rate. CONCLUSION: Palliative resection surgery for primary colorectal cancer is associated with a higher median survival rate. Also, the presence of liver metastasis and tumor size are associated with poor survival. Therefore, resection of the primary tumor should be considered in patients with non-curable colon cancer.

Crohn's disease activity index and Vienna classification--is it worthwhile to calculate before surgery?

BACKGROUND: Crohn's disease (CD) patients with increased disease activity may reveal an increased risk for perioperative complications. The "Crohn's disease activity index" (CDAI) and the "Vienna classification" (VC) were developed for standardized disease activity estimations. The significance of these scores to predict extent, type and early outcome of surgery in CD patients was analyzed. METHODS: In 179 surgically treated CD patients, the CDAI and VC were assessed from a prospective database. Relations of the scores with CD risk factors, type, number, location and complications of surgery were analyzed. RESULTS: VC behavior and location subtypes were associated with distinct types of surgery (i.e. "strictureplasty" in "stricturing disease", "colon surgery" in "colon involvement"), but not with surgery type and extent or outcome. Surgery extent (i.e. with 5 vs. 3 "surgical sites" 425 +/- 25 vs. 223.3 +/- 25) and complications (357.1 +/- 36.9 (with) vs. 244.4 +/- 13 (without)) were associated with elevated CDAI levels; however, nicotine abuse remained the only significant risk factor for perioperative complications after multiple logistic regression. CONCLUSION: The significance of VC or CDAI for predicting the extent of surgery or complications is limited. None of the tested variables except preoperative nicotine abuse influenced the likelihood for perioperative complications.

Expression of BCL-2 in liver grafts after adenoviral transfer improves survival following prolonged ischemia and reperfusion in rat liver transplantation.

UNLABELLED: Apoptosis represents a crucial mechanism of ischemia-reperfusion injury after liver transplantation. Bcl-2 may inhibit apoptosis. This study investigates the effect on ischemia/reperfusion injury and survival after rat liver transplantation of adenoviral bcl-2 transfer into donor livers. METHODS: A nonreplicative adenovirus, expressing bcl-2 under control of a tetracyclin-inducible promoter (adv TetOn bcl-2) was used to treat male Lewis rats in combination with a second adenovirus transferring the TetOn repressor protein under control of a cytomegalovirus promoter (advCMVRep). Virus induction was achieved by addition of doxycyclin to the drinking water. Controls were pretreated with a control adenovirus (advCMV GFP) or with doxycycline. Liver transplantations were performed after 16-hour graft storage. Bcl-2 expression was evaluated by Western blot and immunohistology. Survival was monitored for 7 days, and tissue specimens were collected at 24 hours and 7 days post reperfusion. RESULTS: After pretreatment with advTetOn bcl-2/adv CMVRep, intrahepatic bcl-2 expression was evident at 24 hours and 7 days but was absent among controls. Bcl-2 expression was detected in hepatocytes and, to a high degree, in sinusoidal lining cells. TUNEL-positive sinusoidal lining cells were strikingly reduced after bcl-2 transfer (0.1 +/- 0.3 cells/hpf, mean +/- SD) compared to control virus (4.8 +/- 2.3) or doxycyclin-treated grafts (1.3 +/- 0.2); P < .05. After bcl-2 treatment, survival after transplantation was 100%, whereas it was 50% in both control groups (P = .035). CONCLUSION: The study shows the feasibility of transient, doxycyclin-controlled adenoviral gene transfer in a transplantation model. Bcl-2 expression increased survival after ischemia/reperfusion in rat liver transplantation, potentially through protection of sinusoidal lining cells.

Partitioning of TSE infectivity during ethanol fractionation of human plasma.

The practice of validating processes for their capacity to inactivate a range of non-enveloped and enveloped viruses also provides confidence that plasma products will be safe from emerging viral pathogens with known aetiology. Of greater concern are diseases of unknown or poorly defined aetiology such as the group of neurological diseases collectively called the transmissible spongiform encephalopathies (TSEs), or prion diseases, for which the best known human disease is Creutzfeldt-Jakob Disease (CJD) and its variant form (vCJD). The goal of the current study was to investigate the potential for manufacturing steps used in the production of albumin and immunoglobulin products by Kistler-Nitschmann fractionation, and the utility of nanofiltration of immunoglobulin to remove TSE agents. Two different scrapie model systems were used. In the first system infectious material used for spiking was scrapie sheep brain homogenate with infectivity titres being measured in hamsters. In the second system purified scrapie agent was used (PrP fibrils) with Western blot analysis measuring reduction in the proteinase K resistant form being used as a measure of removal. The data demonstrated substantial removal of the infectious agent by the manufacturing process in both model systems although some differences were observed in partitioning of the two different infectious materials. The hamster infectivity studies were shown to be approximately 1000 fold more sensitive than the Western Blot assay. The data from both studies provide added confidence that these plasma products are safe with respect to their potential to transmit TSE.