Surgical management of large renal tumors

The surgical management of patients with renal cell carcinoma has undergone many changes. With equivalent oncologic outcomes and appreciation of the importance of renal functional preservation, the utilization of nephron-sparing partial nephrectomy has increased in recent years. Nevertheless, tumors of larger size continue to be preferentially treated with radical nephrectomy. Here, we present evidence that improvements in techniques and durability of oncologic outcomes has justified the use of nephron sparing to accomplish renal functional preservation even in patients with large renal tumors. In addition, surgical technical considerations when managing such tumors are discussed. Finally, we discuss cytoreductive surgery and the evolving role of systemic targeted therapies in the management of advanced metastatic disease.     

Surgical management of large renal tumors

The surgical management of patients with renal cell carcinoma has undergone many changes. With equivalent oncologic outcomes and appreciation of the importance of renal functional preservation, the utilization of nephron-sparing partial nephrectomy has increased in recent years. Nevertheless, tumors of larger size continue to be preferentially treated with radical nephrectomy. Here, we present evidence that improvements in techniques and durability of oncologic outcomes has justified the use of nephron sparing to accomplish renal functional preservation even in patients with large renal tumors. In addition, surgical technical considerations when managing such tumors are discussed. Finally, we discuss cytoreductive surgery and the evolving role of systemic targeted therapies in the management of advanced metastatic disease.     

Plant phenolics decrease intestinal tumors in an animal model of familial adenomatous polyposis

Epidemiological studies consistently indicate that consumption of fruits and vegetables lowers cancer risk in humans and suggest that certain dietary constituents may be effective in preventing colon cancer. Plant-derived phenolic compounds manifest many beneficial effects and can potentially inhibit several stages of carcinogenesis in vivo. In this study, we investigated the efficacy of several plant-derived phenolics, including caffeic acid phenethyl ester (CAPE), curcumin, quercetin and rutin, for the prevention of tumors in C57BL/6J-Min/+ (Min/+) mice. These animals bear a germline mutation in the Apc gene and spontaneously develop numerous intestinal adenomas by 15 weeks of age. At a dietary level of 0.15%, CAPE decreased tumor formation in Min/+ mice by 63%. Curcumin induced a similar tumor inhibition. Quercetin and rutin, however, both failed to alter tumor formation at dietary levels of 2%. Examination of intestinal tissue from the treated animals showed that tumor prevention by CAPE and curcumin was associated with increased enterocyte apoptosis and proliferation. CAPE and curcumin also decreased expression of the oncoprotein beta-catenin in the enterocytes of the Min/+ mouse, an observation previously associated with an antitumor effect. These data place the plant phenolics CAPE and curcumin among a growing list of anti-inflammatory agents that suppress Apc-associated intestinal carcinogenesis.     

Mouse colostomy model for studies on large bowel cancer

The development of appropriate animal model systems has been proposed as a means of facilitating the study of human colorectal cancer. This report describes the development and use of a blind-colorectal pouch in a carcinoma mouse model. The blind-pouch was prepared in C57BL/6J mice by surgically exteriorizing the descending colon and producing two stomata in the abdominal wall. The proximal stoma served as an end colostomy and the distal stoma created as a mucous fistula. Surgical closure of the anus thus provided a colorectal pouch. In pilot studies it was found that N-methyl-N-nitrosourea (MNU) and radiation together but neither separately produced tumors in the pouch of surviving mice. Further, inoculation of C38 syngeneic tumor cell suspension into the pouch and immediate closure resulted in tumor takes within three to four weeks. The use of this model in carcinogenesis and the immunology of colon cancer simulate the human colorectal cancer problem more closely than previous animal models.     

Uro-radiographic investigations in patients with tumors in the large bowel (author's transl)]

At the Istituto Nazionale Tumori, from 1970 to 1974, 154 patients with cancer of the large bowel underwent urography; 80 cases before surgery and 74 after surgery. Preoperative findings, correlated with neoplasia, were found in 4 patients, while non-neoplastic lesions were found in 32 patients. During postoperative evaluation, 21 patients showed lesions by locoregional diffusion of the neoplasia with involvement of the ureters especially by metastatic nodes. Less frequent was the finding of bladder involvement. 30 patients presented lesions due to surgery. Urography is useful for evaluating patients with neoplasia of the large bowel, especially after surgery and during follow-up.     

Efficacy of cooling therapy and α-lipoic acid derivative against chemotherapy-induced alopecia in an animal model

Chemotherapy-induced alopecia is frequently induced by various regimens of chemotherapy and has a significant impact on mental health and quality of life. However, the effect of available current treatment for chemotherapy-induced alopecia is not sufficient. This study aimed to clarify the therapeutic effects and mechanism of skin cooling and the antioxidant α-lipoic acid derivative on chemotherapy-induced alopecia. We developed a chemotherapy-induced alopecia model of cyclophosphamide (120 μg/g) using Institute of Cancer Research mice. We used cooling therapy and α-lipoic acid derivative application as the treatments. We compared the alopecia score, hair bulb diameter, insulin-like growth factor-1 level, vascular permeability, and apoptosis between the control and treatment groups. The alopecia score significantly improved in each treatment group compared with that in the cyclophosphamide group. Hair bulb diameter significantly improved in the cyclophosphamide + cooling group compared with that in the cyclophosphamide group. The insulin-like growth factor-1 level and vascular permeability level was significantly retained and suppressed, respectively, in each treatment group compared with that in the cyclophosphamide group. The number of apoptotic cells in the vascular endothelium significantly decreased in the cyclophosphamide + α-lipoic acid derivative group compared with that in the cyclophosphamide group. In conclusion, cooling therapy and α-lipoic acid derivative facilitated recovery from chemotherapy-induced alopecia caused by cyclophosphamide through decreasing vascular permeability.     

Intrapleural administration of lipoplatin in an animal model

Background

Lipoplatin is a new liposomal cisplatin already tested in solid tumors with encouraging results. Little is known about the activity of lipoplatin administered intrapleurally (IP).

Aim

The aim of this study was to assess in an animal model the pharmacokinetics, and potentially induced histopathological lesions of lung and kidney after IP vs. IV injection of lipoplatin.

Methods

15 male Wistar rats were assigned to an IV group at dose 10 mg/kg of lipoplatin (group 1) and to IP groups at 10 (group 2) or 20 mg/kg (group 3) equal to 60 and 120 mg/m² in humans respectively. After lipoplatin administration, serial plasma samples were analyzed by atomic absorption spectrometry for the maximum plasma concentration (C_max), the area under the plasma concentration-time curve (AUC), and the total body clearance (CL). Pleura, lungs and kidneys of the rats were histologically examined for possible lesions.

Results

The C_max was significantly higher in groups 1 vs. 2 (p = 0.02) and vs. 3 (p = 0.01). The AUC of groups 3 vs. 1 was significantly higher (p = 0.028) but the AUC of groups 2 vs. 1 was significantly lower (p = 0.02). CL in IP rats did not differ considerably compared to the IV. Inflammatory changes were noted in the pleura of IP rats and mild kidneys lesions in IV group.

Conclusion

Compared to the IV route, IP20 administration of lipoplatin yielded higher AUC, equal CL, but a significantly lower C_max. As C_max is a determinant of lipoplatin toxicity, IP administration might offer a more effective therapeutic index while improving tolerability. We noted fibrotic changes in the pleura of IP rats, and mild kidneys changes in IV rats, as expected.     

Surgical prophylaxis of peritonitis and other suppurative-inflammatory complications following intra-abdominal resections in cancer of the large intestine

The report discusses a surgical procedure for prevention of pyo-inflammatory complications and peritonitis tested experimentally in 21 rabbits and clinically in 44 patients with colorectal cancers. The frequency of pyo-inflammatory complications was reduced following a reinforcement of anastomosis sutures with autoplastic materials in a procedure employing extraperitonization.     

Mutant Bik expression mediated by the enhanced minimal topoisomerase IIalpha promoter selectively suppressed breast tumors in an animal model

To ensure the success of systemic gene therapy, it is critical to enhance the tumor specificity and activity of the promoter. In the current study, we determined that topoisomerase IIalpha promoter is selectively activated in breast cancer cells. An element containing an inverted CCAAT box (ICB) was shown to be responsible for the breast cancer specificity. When the ICB-harboring topoisomerase IIalpha minimal promoter was linked with an enhancer sequence from the cytomegalovirus immediate early gene promoter (CMV promoter), this composite promoter, CT90, exhibited activity comparable to or higher than the CMV promoter in breast cancer cells in vitro and in vivo, yet expresses much lower activity in normal cell lines and normal organs than the CMV promoter. A CT90-driven construct expressing BikDD, a potent proapoptotic gene, was shown to selectively kill breast cancer cells in vitro, and to suppress mammary tumor development in an animal model of intravenously administrated, liposome-delivered gene therapy. Expression of BikDD was readily detectable in the tumors but not in the normal organs (such as heart) of CT90-BikDD-treated animals. The results indicate that liposomal CT90-BikDD is an effective systemic breast cancer-targeting gene therapy.     

New therapeutic approaches for brainstem tumors: a comparison of delivery routes using nanoliposomal irinotecan in an animal model

Despite the advances in imaging, surgery and radiotherapy, the majority of patients with brainstem gliomas die within 2 years after initial diagnosis. Factors that contribute to the dismal prognosis of these patients include the infiltrative nature and anatomic location in an eloquent area of the brain, which prevents total surgical resection and the presence of the blood–brain barrier (BBB), which reduces the distribution of systemically administered agents. The development of new therapeutic approaches which can circumvent the BBB is a potential path to improve outcomes for these children. Convection-enhanced delivery (CED) and intranasal delivery (IND) are strategies that permit direct drug delivery into the central nervous system and are an alternative to intravenous injection (IV). We treated rats bearing human brainstem tumor xenografts with nanoliposomal irinotecan (CPT-11) using CED, IND, and IV. A single treatment of CED irinotecan had a similar effect on overall survival as multiple treatments by IV route. IND CPT-11 showed significantly increased survival of animals with brainstem tumors, and demonstrated the promise of this non-invasive approach of drug delivery bypassing the BBB when combined with nanoliposomal chemotherapy. Our results indicated that using CED and IND of nanoliposomal therapy increase likelihood of practical therapeutic approach for the treatment of brainstem gliomas.     

Increased mucosal ornithine decarboxylase activity in large bowel with multiple tumors, adenocarcinoma, and adenoma

The polyamine biosynthetase, ornithine decarboxylase (ODC), involved in tumor promotion, was investigated in grossly normal mucosa obtained from surgically resected large bowel; 48 cases with and six cases without large bowel cancer. The mucosal ODC activity was significantly higher in 17 multiple tumor cases bearing adenocarcinoma(s) plus adenoma(s) than in 31 solitary tumor cases bearing one adenocarcinoma alone. It was higher in the mucosa of the two groups of cases than in the mucosa of individuals without large bowel cancer. Furthermore, the enzyme activity in left-sided cancer cases was significantly higher than that in right-sided cancer cases. Carcinoma tissue showed a remarkable high level of enzyme activity, compared with the normal mucosa. The results indicate the larger the number of tumors the higher the level of the ODC activity in the normal mucosa, particularly in left-sided cancer cases. It is concluded that the mucosal ODC may provide a good biological marker to detect individuals at higher risk for large bowel cancer due to exogenous or endogenous factors, and thus contribute to the prevention of mortality from large bowel cancer.     

Fudr as an adjuvant to surgery in cancer of the large bowel

In a controlled trial the Veterans Administration Surgical Adjuvant Group studied 735 patients with carcinoma of the large bowel in an effort to determine the possible benefits of using FUDR as an adjuvant to surgical resection. Patients randomized to treatment received a reduced course of the drug on the first, second, and third postoperative days, and a second standard therapeutic course approximately six weeks later. There was no significant difference in postoperative complications or 30 day mortality. The second course of chemotherapy was an apparent contributory factor in the death of six patients. Long term follow-up studies showed no difference in survival between patients receiving the drug and those treated by surgery alone.     

Antimetastatic effect of amiloride in an animal tumour model

The diuretic Amiloride competitively inhibits the catalytic activity of the urokinase-type plasminogen activator on plasminogen in vitro. This effect was tested on a rat adenocarcinoma model and its invasive potential in the host lung. While the inhibitory effect on intact cell cultures of the tumour was slight, continuous exposure of tumour-injected animals to the drug completely prevented the formation of lung metastasis.     

The role of colon fibroblasts in malignant large bowel obstruction--an experimental in vitro model

The mechanism of bowel obstruction in colorectal cancer is likely to involve interactions between tumour cells, host fibroblasts and the extracellular matrix. The role of fibroblast-mediated matrix reorganisation in malignant structures of the large bowel was examined in an in vitro collagen matrix model in which tumour cells and fibroblasts were cultured under serum-free conditions. Colon cancer cells secreted a factor(s) which enhanced the ability of colon fibroblasts to contrast a collagen matrix without an associated mitogenic response by the fibroblasts. Within uncontracted collagen gels marked elongation of fibroblast cell processes was observed in the presence of the tumour-derived factor(s). We propose that matrix reorganisation by host fibroblasts in the wall of the human colon is responsible, at least in part, for malignant large bowel obstruction.     

Surgical antibiotic prophylaxis in a Turkish university hospital

A prospective study was performed to assess the practice of antibiotic prophylaxis for surgical procedures in Pamukkale University Hospital, Denizli, Turkey. All surgical procedures performed between April 1 and July 31, 2001, were included. During the study period 897 operations were reviewed. 96% of all procedures were elective, 4% emergencies. Approximately 70.7% were clean surgery, 25.3% clean-contaminated, 2.8% contaminated, and 1.2% dirty. 98% of patients (879) received antibiotic prophylaxis. Although timing of prophylaxis was appropriate in all procedures, the duration of prophylaxis was optimal in only 47.7% of all cases. Sulbactam/ampicillin (SAM), cefazolin and cefepime were the most commonly used antibiotics during the study period. The results of our study suggest that the choice of prophylactic antimicrobial agent was inappropriate in most cases. In conclusion, we think that compliance regarding the optimal choice, frequency, and duration of perioperative antibiotic prophylaxis is not adequate in our hospital, and that more education on the subject is necessary.