Synergistic Effect of Interstitial Laser Coagulation and Doxorubicin in a Murine Tumor Recurrence Model of Solitary Colorectal Liver Metastasis

Background Interstitial laser coagulation (ILC) is gaining acceptance for treatment of unresectable colorectal liver metastases. However, local recurrence rates are still high. To overcome this problem, we investigated the potential of additional systemic therapy after ILC in a murine model. Methods Single C26 colon carcinoma nodules (∼1 mm³) expressing firefly luciferase were implanted in the left liver lobe of 32 BALB/c mice. Seven days after implantation, tumors were treated with either ILC alone (neodymium–yttrium aluminum garnet; 6 W/cm; 800 J/cm) or ILC followed by 1 mg/kg of doxorubicin intravenously. Controls received either doxorubicin alone or sham treatment. Tumor load was measured by in vivo bioluminescent imaging. Results Solitary colorectal liver metastases developed over 7 days after tumor implantation in the liver. Extrahepatic disease was not observed. The ILC dose was set to ablate the liver metastases with recurrent tumor growth in 9 of 16 mice after 7 days. After ILC plus doxorubicin, complete tumor destruction occurred without recurrence (0 of 14). Sham treatment or treatment with doxorubicin alone showed an exponential increase in tumor load. Conclusions A murine tumor recurrence model after local ablative treatment of solitary liver metastasis was developed. The combination of ILC and doxorubicin had a strong synergistic effect that led to complete tumor remission in all animals treated.     

Long-term Survival of Patients with Unresectable Colorectal Liver Metastases treated by Percutaneous Interstitial Laser Thermotherapy

In situ ablation of colorectal cancer (CRC) liver metastases is an accepted form of treatment for selected patients. It is associated with low morbidity and mortality and increases the number of patients who may benefit from therapy compared to resection alone. This study assesses the impact of interstitial laser thermotherapy (ILT) on local tumor control and long-term survival in patients with unresectable CRC liver metastases. Percutaneous ILT was performed in patients with unresectable CRC liver metastases between January 1992 and December 1999 using a bare-tip quartz fiber connected to an Nd:YAG laser source. This was prior to the routine use of a diffusing fiber for ablative therapy. Treatment was monitored with real-time ultrasonography. Tumors were considered unresectable based on their anatomic location or the extent of liver involvement. Patients with extrahepatic disease, more than five liver metastases, or tumors larger than 10 cm in diameter were excluded from this study. Local tumor control was assessed by dynamic computed tomography (CT) 6 months after therapy. Long-term follow-up was undertaken, and the impact of various factors on survival was analyzed. Eighty patients with a mean age of 63.8 years were suitable for ILT. In total, 168 liver tumors with a median diameter of 5 cm (range 1–10 cm) were so treated. There were no procedure-related deaths. The overall complication rate was 16%, with all cases managed conservatively. Bradycardia (n = 5), pneumothorax (n = 3), and persistent pyrexia (n = 3) were the most common complications. Complete tumor ablation was noted in 67% of patients assessed by CT 6 months following the initial therapy. Median follow-up was 35 months (range 4–96 months), with 10 patients alive at the end of this period. Altogether there were 67 deaths, which were related to hepatic disease in 55 cases and to extrahepatic disease in 9; they were unrelated to malignancy in 3 others. Three patients were excluded from follow-up after ILT down-staging of tumors that allowed complete surgical resection. The median disease-free survival of patients treated by ILT was 24.6 months, with a 5-year survival of 3.8%. Poor tumor differentiation and the presence of more than two hepatic metastases were associated with lower overall survival (p < 0.01). Fourteen patients treated by ILT for postoperative hepatic recurrences had the best outcome, with a median overall survival of 36.3 months and a 5-year survival of 17.2%. Percutaneous ILT is a minimally invasive, safe, effective technique that appears to improve overall survival in specific patients with unresectable CRC liver metastases, compared to the natural history of untreated disease reported in the literature.     

Radioimmunotherapy Improves Survival of Rats with Microscopic Liver Metastases of Colorectal Origin

Background  Half of the patients with colorectal cancer develop liver metastases during the course of their disease. The aim of the present study was to assess the efficacy of radioimmunotherapy (RIT) with a radiolabeled monoclonal antibody (mAb) to treat experimental colorectal liver metastases. Methods  Male Wag/Rij rats underwent a minilaparotomy with intraportal injection of 1 × 10⁶ CC531 tumor cells. The biodistribution of ¹¹¹In-labeled MG1, 1 day after intravenous administration, was determined in vivo and compared with that of an isotype-matched control antibody (UPC-10). The maximal tolerated dose (MTD) of ¹⁷⁷Lu-labeled MG1 was determined and the therapeutic efficacy of ¹⁷⁷Lu-MG1 at MTD was compared with that of ¹⁷⁷Lu-UPC-10 and saline only. RIT was administered either at the day of tumor inoculation or 14 days after tumor inoculation. Primary endpoint was survival. Results   ¹¹¹In-MG1 preferentially accumulated in CC531 liver tumors (9.2 ± 3.7%ID/g), whereas ¹¹¹In-UPC-10 did not (0.8 ± 0.1%ID/g). The MTD of ¹⁷⁷Lu-MG1 was 400 MBq/kg body weight. Both the administration of ¹⁷⁷Lu-MG1 and ¹⁷⁷Lu-UPC-10 had no side-effects except a transient decrease in body weight. The survival curves of the group that received ¹⁷⁷Lu-UPC-10 and the group that received saline only did not differ (P = 0.407). Administration of ¹⁷⁷Lu-MG1 RIT immediately after surgery improved survival significantly compared with administration of ¹⁷⁷Lu-UPC-10 (P = 0.009) whereas delayed treatment did not (P = 0.940). Conclusion  This study provides proof of principle that RIT can be an effective treatment modality for microscopic liver metastases, whereas RIT is not effective in larger tumors.     

Liver Resection of Colorectal Liver Metastases in Elderly Patients

Background  

The percentage of elderly patients with colorectal liver metastases (CLM) has increased. Liver resection remains the only curative therapy; data evaluating the outcome in this age group is limited. Aim of the present study was to determine if postoperative morbidity, mortality, and other independent predictors influence survival in patients ≥70 years undergoing liver resection for CLM.     

Tubular Contents of Equine Dentin: A Scanning Electron Microscopic Study

The dentinal tubules of 20 permanent equine incisors were investigated by scanning electron microscopy. Occlusal surfaces and longitudinal fracture planes of both etched and undecalcified teeth were examined. Three different types of structure were observed inside the dentinal tubular lumen. Odontoblastic processes could only be visualized in the circumpulpal parts of the tubules. The more peripheral parts were empty or housed cylindrical structures that probably correspond to the laminae limitantes. Collagen fibres were frequently observed in the tubular lumina and were most numerous in the circumpulpal parts of the tubules.     

Electron Microscopic Study of Interstitial Cells in Cryptorchid Human Testes. I: Interstitial Cells in Prepubertal Age

In order to establish the ultrastructural features of Leydig cells 50 biopsies or prepubertal human cryptorchid testes have been examined. Light and electron microscopic observations reveal the presence of two types of interstitial cells distinguishable on the basis of the peculiar ultrastructural characteristic of the nucleus and cytoplasm. In our opinion these two types of interstitial cells seem to represent different stages of cell differentiation. There are fibroblast-like cells and cells corresponding to Leydig cells. From our observations it may be inferred that the fibroblast-like cells are the precursor cells of the Leydig cells.     

Colorectal Liver Metastases: State of the Art Imaging

Colorectal cancer is a leading cause of death with mortality determined predominately by metastatic involvement of the liver. Treatment of liver metastases continues to evolve and imaging plays an essential role in initial staging, preoperative planning, and treatment monitoring. This review article discusses the current role of imaging in the management of patients with colorectal liver metastases. Particular challenges such as hepatic steatosis, disappearing metastases, and following treated lesions are addressed.     

Multiagent Chemotherapy for Isolated Colorectal Liver Metastases: A Single-centered Retrospective Study

Background  Few studies identifying variables associated with prognosis after resection of colorectal liver metastases (CLM) account for treatment with multiagent chemotherapy (fluoropyrmidines with irinotecan, oxaliplatin, bevacizumab, and/or cetuximab). The objective of this retrospective study was to determine the effect of multiagent chemotherapy on long-term survival after resection of CLM. Methods  Demographics, clinicopathologic tumor characteristics, treatments, and long-term outcomes were reviewed. Results  From 1996 to 2006, 230 patients underwent resection of CLM. Treatment strategies before and after resection included fluoropyrimidine monotherapy (n = 34 and n = 39), multiagent chemotherapy (n = 81 and n = 73), and observation (n = 115 and n = 118). Prehepatectomy treatment strategy was not associated with overall survival. Actuarial 4-year survival was 63%, 39%, and 40% for patients treated with multiagent chemotherapy, fluoropyrimidine monotherapy, and observation after hepatectomy, p = 0.06. Posthepatectomy multiagent chemotherapy (p = 0.04, HR 0.52 [0.27–1.03]), duration of posthepatectomy chemotherapy treatment of 2 months or longer (p = 0.05, HR 0.49 [0.25–0.99]), carcino-embryonic antigen level >10 ng/mL (p = 0.03, HR 2.09, 95% CI [1.32–3.32]), and node positive primary tumor (p = 0.002, HR 1.79 [1.06–3.02]) were associated with overall survival in multivariate analysis. Conclusions  The association of posthepatectomy multiagent chemotherapy with overall survival in this retrospective study indicates the need for prospective randomized trials comparing multiagent chemotherapy and fluoropyrimidine monotherapy for CLM.     

On the Microscopic Anatomy of the Rete Testis A Scanning Electron Microscopic and Light Microscopic Study

The microscopic anatomy of the transitional zone of the seminiferous tubules, the tubuli recti and the rete testis in adult rats was studied with histological serial sections, semithin sections and scanning electron microscopy. In paraffin section most transitional zones of the seminiferous tubules seemed to be obliterated by the modified Sertoli cells. Thinner plastic sections showed always a lumen, however. PAS - positive material, throught to represent masses of degenerating spermatozoa surrounded by Sertoli cell nuclei was found in 20% of transitional zones. About 80% of the tubuli recti had an initial widening which surrounded the bulging Sertoli cell bodies of the transitional zones.
The intratunical rete consisted of five to seven intercommunicating channels, usually of small caliber. One wide communication was regularly present, however. The extratesticular rete was usually formed of two wide cavities. From their subdivisions the five to seven ductuli efferentes arose. The rete epithelium varied from very thin squamous to cuboidal and even columnar. The epithelial cells contained a flagellum surrounded by peripheral microvilli. Loose connective tissue was found under the epithelium of all parts of the rete.     

Scanning Electron Microscopic Study on Double and Single Eyelids in Orientals

The conventional theory is that Occidentals have a terminal insertion of the levator aponeurosis at the anterior portion, resulting in a double eyelid, whereas in Orientals this fiber is not present, and therefore results in a single eyelid have been anatomically demonstrated. However, there have been more than a few reports indicating that the anatomical difference between a single eyelid and double eyelid in Orientals cannot be explained by this theory. Therefore, in order to verify the direction of the levator aponeurosis in the eyelids of Orientals, we observed Japanese eyelids using a scanning electron microscope (SEM). As a result of three-dimensional, cross-sectional observations using SEM, we were able to confirm the existence of a branch of the levator aponeurosis that runs through the layer of the orbicularis oculi muscle and connects with the levator aponeurosis in the double eyelid, as in the occidental eyelid. This was not seen in the single eyelid. It is thought that this new anatomical finding will become an important fundamental for double eyelid operations in Orientals.     

Extending the Limits of Resection for Colorectal Liver Metastases: Positive Resection Margin and Outcome After Resection of Colorectal Cancer Liver Metastases

Journal of Gastrointestinal Surgery -     

老年结直肠癌肝转移的治疗

目的 总结老年结直肠癌肝转移(CRCLM)治疗的现状,探讨老年CRCLM治疗的方法 和原则.方法 复习国内、外近年来有关老年CRCLM治疗的相关文献并作综述.结果 结直肠癌是消化系统最常见的恶性肿瘤,而最常见的转移部位是肝脏.近年来,老年结直肠癌发病率逐渐升高.虽然同年轻患者比较,老年CRCLM患者的身体状态和生理机能较差,但只要选取合适的病例,同样可以获得与年轻患者相似的治疗效果.目前,对于可切除的CRCLM患者,惟一可能治愈的手段仍然是外科手术治疗;而化疗和分子靶向药物治疗的最新进展,也让更多的老年患者生存获益.对于不可切除的CRCLM病灶尚可结合其他肝脏导向的局部治疗方法,如局部化疗、消融治疗等.结论 根据CRCLM的发病特点和老年患者的自身特点,采用多学科协作模式下的个体化治疗模式,可进一步提高老年CRCLM患者的综合治疗效果.     

Chemotherapy-Associated Liver Injury: Impact on Surgical Management of Colorectal Cancer Liver Metastases

Chemotherapy is integral to the management of patients with advanced colorectal cancer liver metastases. Due to their improved efficacy, modern regimens can sometimes convert unresectable disease to a resectable state. As chemotherapy is often administered prior to hepatic resection, adverse effects on the liver are increasingly being recognized. Investigators have identified a wide spectrum of effects on the underlying liver parenchyma, ranging from mild forms of steatosis to severe steatohepatitis and sinusoidal obstruction syndrome. As the histopathologic definitions of these changes evolve, studies have identified specific patterns of hepatic injury related to the various chemotherapeutic agents. The impact of these changes on perioperative outcome after partial hepatectomy remains controversial. Timing and duration of chemotherapy may play a key role and account for discrepancies in outcomes seen among studies. In this review, we provide an overview of the spectrum of chemotherapy-associated liver injury and discuss its relevance to perioperative management of patients undergoing hepatic resection of colorectal cancer liver metastases.     

Polytetrafluoroethylene and Anodized Aluminum Surfaces in an Extracorporeal Circuit: Scanning Electron Microscopic Study

Tubes with polytetrafluoroethylene (PTFE) or anodized aluminum surfaces were inserted in an extracorporeal circuit which was connected to mongrel dogs. The tubes were removed at regular intervals during the perfusions and their inner surfaces were examined by scanning electron microscopy. The anodized aluminum tubes were covered with platelets, fibrin, and other blood elements in a thick layer. In contrast, the PTFE tubes were mainly uncovered.     

Timing of Resection of Liver Metastases Synchronous to Colorectal Tumor: Proposal of Prognosis-Based Decisional Model

Background Timing of hepatectomy for synchronous metastases of colorectal cancer is still debated. The aim of this retrospective study was to analyze prognostic factors after synchronous and delayed liver resections to define selection criteria for choosing timing of hepatectomy. Methods The study was performed on 127 patients with synchronous metastases undergoing radical hepatectomy. We divided patients according to the timing of hepatectomy: 70 synchronous (group A) and 57 delayed (group B). Results Overall survival was similar between the two groups (5-year survival 30.8% vs. 32.0% A vs. B, P = .406). The multivariate analysis evidenced four independent prognostic factors in group A: male sex (P = .04), T4 (P = .0035), more than three metastases (P = .0001), and metastatic infiltration of nearby structures (P < .0001). There were no statistically significant prognostic factors in group B. Patients with more than three metastases had a significantly worse survival in group A than in group B (3-year survival, 15.0% vs. 34.3%, P = .007); similarly, borderline significant difference was encountered in patients with T4 primary tumor (3-year survival, 16.7% vs. 60%, P = .064) Conclusions Patients with liver metastases synchronous with colorectal cancer with T4 primary tumor, metastasis infiltration of neighboring structures, and especially with more than three metastases should receive neoadjuvant chemotherapy before liver resection.     

Outcome of Microscopic Incomplete Resection (R1) of Colorectal Liver Metastases in the Era of Neoadjuvant Chemotherapy

Background  

Data from patients with colorectal liver metastases (CRLM) who received neoadjuvant chemotherapy before resection were reviewed and evaluated to see whether neoadjuvant chemotherapy influences the predictive outcome of R1 resections (margin is 0 mm) in patients with CRLM.