Exophytic condyloma: are they as benign as we think?

AIM: As the understanding of anal dysplasia continues to develop, controversy remains regarding treatment of these lesions. The purpose of this study was to evaluate lesion type (flat vs exophytic) and the association between morphology and dysplasia. METHODS: This was a single-centre retrospective analysis of a prospectively collected pathological database of patients > 17 years old who underwent operative excision/biopsies for presumed anal condyloma or dysplasia from 2009 to 2018. The analysis includes comparisons between patient factors, phenotype and grade of dysplasia. RESULTS: Sixty-nine patients had 423 lesions. The mean age of the study population was 48.2 years. 62.3% were men and 46.4% of patients were black. 47.8% of patients were human immunodeficiency virus (HIV) positive and 39.1% were men who have sex with men (MSM). There were 176 (41.6%) flat lesions and 234 (55.3%) exophytic lesions. Exophytic lesions were 2.5-fold more likely to be associated with a higher grade of dysplasia than flat lesions (OR 2.63, 95% CI 1.09-6.32). Neither lesion type nor dysplasia severity was associated with human papillomavirus, lesion location or patient characteristics, including race, MSM or HIV status. DISCUSSION: Exophytic lesions were more than twice as likely to have advanced dysplasia compared with flat lesions. A clearer understanding of the association between gross lesion appearance and dysplasia will allow more appropriate counselling of patients and the development of better screening and treatment guidelines for anal condylomata and dysplasia.

Is sarcopenia a better predictor of complications than body mass index? Sarcopenia and surgical outcomes in patients with rectal cancer.

AIM: Sarcopenia, or a reduction of lean muscle mass, is associated with poorer outcomes in cancer patients. Few previous studies have examined this potentially correctable risk factor in patients with locally advanced rectal cancer. METHOD: Skeletal muscle mass index was measured retrospectively on initial staging CT scans of patients undergoing chemoradiation followed by radical resection for rectal cancer for the period 2007-2013. Patients were categorized as sarcopenic or nonsarcopenic and differences in terms of demographics, pre-, peri- and postoperative outcomes were examined. RESULTS: Forty-seven patients were included; their mean age was 59.3 (36-82) years and 61.7% were men. We considered that 55.2% of men and 44.4% of women were sarcopenic; the overall prevalence of sarcopenia was 51.1%. Age, preoperative haemoglobin and albumin were significantly related to sarcopenia. Body mass index (BMI) and obesity (BMI > 30 kg/m2 ) were not associated with sarcopenia. Blood transfusions were more frequent in sarcopenic patients (P = 0.001). Although readmissions and length of stay were not increased, overall postoperative complications were significantly higher in sarcopenic patients (P = 0.03). Neither BMI nor obesity was associated with postoperative complications. CONCLUSION: Sarcopenia was present in over 50% of patients with locally advanced rectal cancer at diagnosis. It was associated with a higher incidence of both blood transfusion and postoperative complications. BMI did not correlate with these negative outcomes. Sarcopenia may be a better predictor of surgical outcomes than BMI or obesity.

Transanal endoscopic microsurgery.

Transanal endoscopic microsurgery, or TEM, is a technique that can be used for the treatment for early staged rectal cancer. This technique utilizes carbon dioxide insufflation through a 40 mm rectoscope to create better endoscopic visualization of the operative field. TEM has been praised for its access to middle and upper-third rectal cancers. However, one limitation of TEM is its inability to address local lymph node involvement. Therefore, an adequate preoperative assessment is crucial before using TEM as a curative modality. TEM can be used to remove virtually any benign lesion that can be brought into view. In addition, there are several studies that have shown TEM is a safe and effective way to treat T1 cancers and may have a role in the treatment of T2 and T3 cancers when combined with radiation and chemotherapy. TEM has lower recurrence rates, faster recovery, and fewer complications when compared to other local excision techniques and radical surgeries. The future of TEM is growing in acceptance as more surgeons learn to master this technique.

[Leflunomide reduces the angiogenesis score and tumor growth of subcutaneously implanted colon carcinoma cells in the mouse model]. / Leflunomid reduziert den Angiogenesescore und das Tumorwachstum subkutan implantierter Kolonkarzinomzellen im Mausmodell.

BACKGROUND: The inhibition of tumorangiogenesis may be of importance in the additive treatment of various cancers. Leflunomide, a drug which has been approved in Germany for the therapy of rheumatoid arthritis, inhibits the activity of several growth factors in vitro. The aim of this study was to investigate the effects of the drug on tumor angiogenesis in a nude mouse model. MATERIALS AND METHODS: A total of 40 nude mice were injected with human colon carcinoma cells. Following randomization in 4 groups, therapy started on day five. Group 1 was treated daily with orally administered Leflunomide (35 mg/kg) dissolved in 1.5% Carboxymethylcellulose (CMC). Group 2 served as a control group and received 1 ml CMC orally per day. The animals of group 3 were treated daily with 35 mg Leflunomide/kg KG and 500 mg Uridine/kg dissolved in 1 ml Nacl 0.9% intraperitoneally. The 4th group again served as a control group and received only 500 mg Uridine/kg intraperitoneally each day. The main outcome criterion was the angiogenesis score (AS). In addition, the tumor volume and tumor weight were also assessed. The AS was determined by immunohistochemistry using an antibody against factor VIII related antigen. RESULTS: All animals tolerated the procedure well. In the Leflunomide and the Leflunomide/Uridine group the angiogenesis score (p < 0.01), the tumor volume (p < 0.01) and the tumor weight (p < 0.01) were lower compared to the respective control groups. CONCLUSION: The administration of Leflunomide leads to a significant reduction of tumor weight and tumor volume following subcutaneous injection of human colon carcinoma cells in a nude mouse model. This could be due to the reduction of tumor angiogenesis. Following further experimental and clinical studies, Leflunomide may come to play a role in the additive treatment of colonic carcinoma.

Do angiogenesis and growth factor expression predict prognosis of esophageal cancer?

A retrospective study of surgically resectable esophageal cancers was undertaken to determine the relationship between angiogenesis score and growth factor expression with tumor size, histology, degree of differentiation, depth of invasion, nodal disease, and the presence of Barrett's esophagus. The office and hospital charts of 27 patients who had esophageal resection for carcinoma between 1990 and 1995 at Rush-Presbyterian-St. Luke's Medical Center were reviewed. Data collection included patient demographics, survival, tumor size, histology, differentiation, depth of invasion, nodal metastases, and the presence of Barrett's esophagus. The pathology specimens were immunostained for von Willebrand factor (factor VIII-related antigen). Immunostaining was also performed for vascular endothelial growth factor and transforming growth factor alpha. Twenty normal esophageal specimens served as controls. Angiogenesis score was determined by counting vessels under conventional light microscopy at x200 magnification, and growth factor expression was graded on a scale of 1 to 4. Cancers had higher angiogenesis and growth factor expression than controls (P = 0.01). Patient age, tumor size, histology, differentiation, depth of invasion, and Barrett's esophagus did not correlate with angiogenesis score or tumor growth factor expression. Lymph node status did correlate with both angiogenesis score and growth factor expression (P < or = 0.02). We conclude that high angiogenesis score and growth factor expression correlate with the presence of lymph node metastases. This may help select patients for preoperative radiation and chemotherapy or determine the extent of surgery performed for esophageal carcinoma.

Liver resection for colorectal cancer: liver metastases in the aged.

The purpose of this study was to determine the morbidity and mortality in elderly patients undergoing liver resections for metastatic colon cancer and compare them with those of a control group of younger patients. The charts of all patients undergoing liver resection for colon cancer were retrospectively reviewed. Patients less than 70 years of age (Group A) were compared with patients 70 years of age or older (Group B). Between 1971 and 1995, 167 liver resections were performed for metastatic colorectal cancer. Of these, 41 patients were in Group A and 126 patients were in Group B. The mean age of Group A was 74.5 years, and that of Group B was 57 years. American Society of Anesthesiologists (ASA) classification was similar for both groups (Groups A and B were 75.6% and 81.1% ASA class II, respectively). Anatomic resections were performed in 49 per cent and wedge resections in 51 per cent of patients in Group A, and 68 and 32 per cent in Group B, respectively. Estimated blood loss was slightly less for Group A (1575 vs 1973 cm3), as was operative time (4.0 vs 4.7 hours). In-hospital mortality rate was 7.3 per cent for Group A and 2.4 per cent for Group B. The major morbidity rates were 29 and 17.5 per cent, respectively. Intensive care unit care was necessary in 73 per cent (mean length of stay 3.9 days) for Group A and 62.6 per cent (mean length of stay 2.0 days) for Group B. The average length of hospitalization was 13.1 days for Group A and 16.6 days for Group B. The recurrence rates were similar for the two groups [56% (Group A) vs 66% (Group B)], but mean survival was longer for younger patients (22.9 vs 33.5 months). We conclude that liver resection for colorectal cancer liver metastases in properly selected patients older than 70 years of age can be performed with acceptable morbidity and mortality rates. The long-term survival for older patients is less than that for younger patients, but is still a significant length of time. Therefore, we conclude that age alone is not a contraindication to liver resection for colorectal cancer metastases in patients older than 70.

First report of hepatic lobectomy for metastatic carotid body tumor.

Hepatic lobectomy for metastatic colon cancer is well accepted, yielding a 30-35% five-year survival with a low mortality of less than 5%. Less commonly is hepatic resection for selected metastasis from other organs. We report here what we believe is the first hepatic lobectomy for a metastatic carotid body tumor. The patient was a 41-year-old white female who presented with a large incapacitating hepatic metastasis and an incidental lung metastasis from a carotid body tumor resected 12 years earlier. The patient underwent left hemihepatectomy and local lymph node dissection at our university. Twenty-one months after the operation the patient is asymptomatic and has no sign of tumor reoccurrence . We discuss here the clinical features, pathophysiology, treatment and the surgical literature of this rare entity. This is yet another example of the effectiveness of hepatic resection for noncolonic metastasis (26 references).

Evolving trends in the treatment of anorectal diseases.

During the first half of this century, the safe and effective treatment of benign anorectal disorders perhaps did more to establish our specialty as a viable and distinct entity than anything else. A thorough understanding of anorectal anatomy and physiology, improved methods of local anesthesia, and an appreciation of proper postoperative care made the care of patients with diseases of the rectum and anus the domain of true specialists. Hirschman stated, "It is the action of the profession itself which has created the special field of proctology--the anus and rectum being organs peculiar to themselves and being subject to many medical and surgical diseases in the same way as the eye, the ear, the nose, the genital and urinary organs; and call for just as much special medical and surgical care. The general surgeon knows nothing about, and cares less for, the medical treatment of these organs; and the general practitioner who is able to treat the medical conditions is not, as a rule, properly equipped to do so. Thus, the proctologist came into existence--a man who, by special study of this particular region of the body, is able to give special care of either a surgical or medical nature, and often both in the same case, as may be required."

In vitro and in vivo antitumor activity of a novel immunomodulatory drug, leflunomide: mechanisms of action.

Leflunomide, a novel immunomodulatory drug, has two biochemical activities: inhibition of tyrosine phosphorylation and inhibition of pyrimidine nucleotide synthesis. In the present study, we first showed that A77 1726 [N-(4-trifluoromethylphenyl-2-cyano-3-hydroxycrotoamide)], the active metabolite of leflunomide, was more effective at inhibiting the tyrosine kinase activity of platelet-derived growth factor (PDGF) receptor than that of epidermal growth factor (EGF) receptor, and had no effect on the tyrosine kinase activity of the fibroblast growth factor receptor. In the presence of exogenous uridine, A77 1726 was more effective at inhibiting the PDGF-stimulated proliferation of PDGF receptor-overexpressing C6 glioma than the EGF-stimulated proliferation of EGF receptor-overexpressing A431 cells. In vivo studies demonstrated that leflunomide treatment strongly inhibited the growth of the C6 glioma but had only a modest effect on the growth of the A431 tumor. Uridine co-administered with leflunomide did not reverse the antitumor activity of leflunomide on C6 and A431 tumors significantly. Quantitation of nucleotide levels in the tumor tissue revealed that leflunomide treatment significantly reduced pyrimidine nucleotide levels in the fast-growing C6 glioma but had no effect on the relatively slow-growing A431 tumor. Whereas uridine co-administration normalized pyrimidine nucleotide levels, it had minimal effects on the antitumor activity of leflunomide in both tumor models. Immunohistochemical analysis revealed that leflunomide treatment significantly reduced the number of proliferating cell nuclear antigen-positive cells in C6 glioma, and that uridine only partially reversed this inhibition. These results collectively suggest that the in vivo antitumor effect of leflunomide is largely independent of its inhibitory effect on pyrimidine nucleotide synthesis. The possibility that leflunomide exerts its antitumor activity by inhibition of tyrosine phosphorylation or by a yet unidentified mode of action is discussed.

Transanal endoscopic microsurgery: a single surgeon's experience.

OBJECTIVE: To evaluate a single surgeon's experience with transanal endoscopic microsurgery (TEM) with regard to incidence of complications, recurrence rate of benign and malignant lesions, and impact on the treatment of rectal cancer. DESIGN: Prospective tumor registry. SETTING: Tertiary care university hospital. PATIENTS: Seventy-three patients undergoing TEM between January 1991 and November 1996. MAIN OUTCOME MEASURES: Complications, recurrence rates, and use of this technique with respect to radical operations. RESULTS: The arrival of TEM was associated with an increase in the number of operations for rectal cancer; however, the use of TEM remained constant relative to radical resections. Use of TEM resection alone is appropriate for all adenomas and cancers staged Tis and T1. Use of TEM alone is not an appropriate treatment for T2 cancers. Four patients (5%) experienced fecal soilage, which was long lasting in only 1 (1%). CONCLUSIONS: Transanal endoscopic microsurgery is a safe technique and provides improved access to lesions in the middle and upper rectum. Thus far, it has not had a significant impact in the overall treatment of rectal cancer.

Endorectal ultrasound.

Endorectal ultrasound is a very useful diagnostic adjunct for benign and malignant anorectal diseases. The only prerequisite in performing this test is that the examiner appreciate the impact that EUS has on the clinical management of patients. For example, the information obtained when scanning rectal cancer dictates whether local excision (i.e., sphincter preservation) or preoperative adjuvant therapy followed by radical resection is chosen. For benign disease, EUS helps direct therapy for patients with fecal incontinence and selects those patients most likely to benefit from reconstructive surgery.

Mechanical, histologic, and biochemical effects of canine rectal formalin instillation.

UNLABELLED: Instillation of 4 percent formalin effectively treats radiation hemorrhagic proctitis; however, little is known regarding its side effects. PURPOSE: The study contained herein was undertaken to determine rectal compliance and collagen content, mucosal and vascular histologic changes, and kinetics of formalin absorption following instillation. METHODS: Fifteen mongrel dogs (50-60 pounds) were randomized into five experimental groups according to time elapsed from formalin treatment: control, acute, one week, two weeks, and four weeks. Formalin was instilled in 30-ml aliquots to a total volume of 400 ml. Rectal compliance (closed manometry system) was assessed pre-formalin and post-formalin at the designated time interval. Serum formalin metabolites were determined at time 0, 0.5, 1, and 3 hours. A segment of rectal wall was analyzed for collagen content, mucosal injury, and blood vessel density. RESULTS: Serum formalin levels peaked within 30 minutes, returning to normal by 3 hours. With the exception of one dog, toxic levels were not reached at any time during the study. No dogs experienced sepsis, fever, or altered gastrointestinal function. Acute and one-week dogs showed mild diffuse proctitis and mucosal slough, which healed within two weeks. Rectal compliance and collagen content were unchanged. Mucosal blood vessels decreased in number early (P = 0.03). CONCLUSIONS: Instillation of 4 percent formalin in sequential aliquots of a small volume that is kept in contact for a short period of time is safe. Serum formalin levels generally do not reach toxic levels, and the slight elevation in formalin concentration that was seen returns to normal within three hours. Formalin-induced proctitis heals within two weeks, and no long-term changes in rectal compliance or collagen content were seen.

Aminothiol WR-1065 protects endothelial cell morphology against alterations induced by lipopolysaccharide.

In septic patients, lipopolysaccharide (LPS) damages the vascular endothelium, which manifests as tissue edema and impaired healing. This pathology occurs when LPS distorts endothelial cell morphology partly by generating free radicals. A radioprotector that scavenges free radicals, the aminothiol WR-1065 ([N-2-mercaptoethyl]-1-3-diaminopropane) was found in a prior study to normalize the morphology of irradiated endothelial cells (Mooteri SN, Podolski JL, Drab EA, et al: Radiat Res 145:217-224, 1996). The aim of this study was to determine whether WR-1065 also normalized endothelial cell morphology following exposure to LPS. For this aim, portions of bovine aortic endothelial cell cultures were denuded and exposed to LPS at 1 ng/mL. After 30 min, the apical membrane expressed increased integrin receptor to fibronectin, alpha5beta1. After 5 h, the morphology of the cells at the leading edge was distorted, and cell-cell contact was lessened. Also, filamentous actin-containing stress fibers were dissipated; however, filamentous actin content per cell was unchanged. Treatment with 2 mM WR-1065 for 2 h prior to LPS exposure attenuated the increased expression of alpha5beta1 and promoted cell-cell contact in the migrating endothelial cells. WR-1065 also promoted the retention of stress fibers and actin cytoskeletal shape in cells treated with LPS. Thus, LPS distorted endothelial cell morphology after increasing apical membrane expression of alpha5beta1 and dissipating stress fibers, effects prevented by WR-1065.

Absorption kinetics of rectal formalin instillation.

Formalin instillation has become an accepted treatment of radiation-induced hemorrhagic cystitis and proctitis since the initial report by Brown in 1969 (Med. J. Aust. 1:23, 1969). Although its use is widespread, no studies have been performed to determine the safest, volume or duration of formalin exposure. The purpose of our study was to determine the optimum technique for instillation and the safety margin regarding the maximum time that formalin can be in contact with the rectal mucosa without causing serum toxicity. In a pilot canine study, 4% neutral buffered formalin was instilled into the rectum in 30 ml aliquots for 60 seconds each after which each aliquot was withdrawn; a total volume of 400 ml was used. Our subsequent experiment involved rectal instillation of a single formalin bolus of 100 ml for 1 hour without removal during this time. Formalin metabolites were measured in the blood and urine to assess toxicity. Results indicate that with the latter technique serum formic acid reaches toxic levels within 15 minutes of instillation and may stay elevated for several hours. Metabolites in the urine similarly increase within 15 minutes, lagging only shortly behind the rise in serum levels. Performing formalin instillation in a series of 30 ml aliquots appears to be a safer treatment, as toxic serum levels were not reached and their slight rise above baseline returned to normal within 3 hours.

Intraoperative ultrasound in the management of liver neoplasms.

The purpose of this study was to determine the impact of intraoperative ultrasound (IOUS) on the management of patients with neoplasms of the liver. Fifty-nine patients with liver neoplasms (primary, 6; metastatic, 53) and without pre- or intraoperative evidence of extrahepatic disease underwent laparotomy for possible liver resection. Preoperative imaging studies included external ultrasound (n = 12), magnetic resonance imaging (n = 11), and/or computed tomography (n = 57). Intraoperative evaluation on all patients included inspection, bimanual palpation, and ultrasonography. External ultrasound, magnetic resonance imaging, and computed tomography identified all intraoperatively confirmed liver neoplasms in 33, 45, and 67 per cent of cases, respectively. Unsuspected neoplasms were identified in 12 patients (20%) by inspection/palpation and in 19 patients (32%) by IOUS. In eight patients (14%), the occult neoplasms were identified only IOUS, and in one patient the neoplasms were identified only by inspection/palpation. Occult neoplasms identified by IOUS were characterized by small size (less than 2 cm). Findings from the intraoperative evaluation, such as unsuspected neoplasms and vascular proximity or invasion, altered the preoperative plan in 20 (34%) patients. Inspection, and particularly palpation, identifies a number of preoperatively unsuspected liver neoplasms. Intraoperative ultrasound, however, is the most sensitive method for detection of liver neoplasms and influences the operative management in a substantial number of patients.

Transanal endoscopic microsurgery.

Traditional methods of excising adenomas and selected carcinomas of the distal rectum provide adequate exposure and acceptable cure rates. Recurrence rates after locally excising adenomas, however, are 12% to 25%, possibly because the limited exposure has led to less than adequate resection margins. Whether or not TEM can yield lower recurrence rates remains to be seen, but this perhaps is not the main reason one should include TEM in his or her armamentarium. Rather, it is the improved exposure, the superior optics, and the opportunity to address lesions in the upper rectum that set TEM apart from conventional instrumentation. One should also keep in mind that these "inaccessible" lesions have been treated heretofore with either a transsacral or transabdominal approach, both of which are accompanied by a lengthy hospital stay and potential morbidity. When considering TEM excision of rectal cancers, proper patient selection cannot be overemphasized. Endorectal ultrasonography can help to determine depth of penetration preoperatively, and TEM can be used with curative intent for those lesions with minimal involvement of the rectal wall. TEM can also be used as a means to palliate the primary tumor of those patients with incurable, disseminated disease. Minimal-access surgery is here to stay. TEM may gain acceptance in this arena, marking a new technology for the treatment of a number of rectal conditions. The considerable skill necessary to perform this operation, combined with the relatively infrequent nature of the pathology addressed, however, will make TEM the domain of only a few surgeons.

Angiogenesis in colorectal cancer.

Angiogenesis is a complicated multistep process involving the breakdown of the endothelial cell basement membrane, digestion of the extracellular matrix, proliferation and migration of endothelial cells toward the angiogenic stimulus, and formation of functioning capillaries. This neovascular network not only provides nutrients for an expanding tumor mass but also a means of dissemination to sites far removed from the primary tumor site. The entire process is mediated by cytokines or growth factors released either by the tumor cells themselves or by endogenous cells within the microenvironment surrounding the tumor. The literature has conclusively shown that those lesions with high angiogenesis scores or microvessel densities are associated with a higher risk of metastases, recurrence, and early patient death. This is especially so for colorectal cancer. Antiangiogenesis therapy holds promise for the future and, in the adjuvant setting, has many theoretical advantages over conventional cytotoxic chemotherapy.

Radiation injuries of the gastrointestinal tract.

Although radiation has proven itself valuable in the treatment of a variety of pelvic malignancies, it is not without serious morbidity. This article has outlined the incidence of acute and chronic injury, ways to prevent the occurrence of complications, and the use of new medical and surgical treatments.

Tumor angiogenesis in pheochromocytomas and paragangliomas.

BACKGROUND: Angiogenesis correlates with growth and likely metastases in several tumors. To determine whether it has a similar role in pheochromocytomas, immunohistochemical staining of factor VIII was done on the tumor tissue of 42 patients. METHODS: Formalin-fixed, paraffin-embedded tissue was obtained from 29 women and 13 men with 24 primary adrenal and 18 extraadrenal pheochromocytomas. Patients were divided into two groups. Group 1 included 32 patients with benign pheochromocytomas, and group 2 included 10 patients with malignant tumors evidenced by capsular or vascular invasion (six), liver metastases (three), or periaortic lymph node metastases (one). Blood vessels highlighted by factor VIII staining of endothelial cells with labeled streptavidin-biotin were counted under light microscopy. Mean vessel count within a 10 mm2 micrometer disk was calculated under x100, x200, and x400 magnification fields. RESULTS: There were no significant differences in patient age or clinical symptoms between the groups. The mean tumor size in group 2 of 8.8 +/- 5.3 cm was larger than the mean of 4.8 +/- 2.8 cm in group 1 (p < 0.005). The mean counts of vessels in the x100, x200, and x400 magnification fields were 102 +/- 48, 40 +/- 18, and 19 +/- 9 in group 1, and 203 +/- 77, 73 +/- 28, and 37 +/- 15 in group 2. The number of blood vessels in group 2 was significantly higher than in group 1 (p < 0.001) in each studied field. CONCLUSIONS: In this study the number of tumor blood vessels correlated with the invasive behavior of pheochromocytomas. Tumor angiogenesis may be useful in determining the likelihood of malignant behavior in pheochromocytomas.