An unusual case of foreskin phimosis after radiotherapy for rectal carcinoma.

Phimosis of the foreskin after radiotherapy for rectal carcinoma is extremely rare and has previously been described only once (2006) in the English-language literature. Combination chemo/radiotherapy is currently the treatment of choice and widely used in the management of various pelvic malignancies. In this report, we describe a rare complication on male genitalia following the radiotherapy for lower rectal cancers. Few days following the completion of radiotherapy, patient developed phimosis of the foreskin, which was successfully treated medically without the need for circumcision. Radiotherapy can bring a great risk of injury to anorectum and its adjacent structures. Risk of phimosis should be considered under the current radiation guidelines and we support the concept of using penile shielding for all radiotherapy procedures in colorectal carcinoma patients.

Review of 120 anal cancer patients.

OBJECTIVE: Chemoradiotherapy is the mainstay of treatment for the majority of patients with anal cancer, with abdominoperineal resection reserved for salvage. The purpose of this study was to evaluate our results after radiotherapy with or without chemotherapy, and/or surgery in terms of overall survival and colostomy free survival in patients with anal cancer. METHOD: A review of patients diagnosed with anal cancer between 1991 and 2004 was performed. The principle end-points of the study were overall and colostomy-free survival. RESULTS: One hundred and twenty patients were identified. The T stage distribution was T1 32, T2 44, T3 19, T4 17 and TX 8. Eighteen patients had clinically involved regional nodes. Eighty patients received radiotherapy as a component of their treatment. Twenty-four of the 80 patients had a colostomy. The most common late toxicity was faecal incontinence. The overall survival and colostomy-free survival rates for all 120 patients were 58% and 79% at 5 years, respectively. For the 80 patients who received radiotherapy, the corresponding figures were 66% and 82% at 5 years, respectively. CONCLUSION: Chemoradiation is effective organ preserving treatment for anal cancer. Grade 1 and 2 faecal incontinence is a relatively common late toxicity experienced by patients.

Molecular markers in Paget disease of the breast.

BACKGROUND AND OBJECTIVES: Molecular markers are increasingly being analyzed in tumor specimens because of their relevance to both prognosis and choice of therapy. Paget disease of the breast is an uncommon form of breast cancer, in which molecular markers have not been well characterized. The objective of this study was to investigate the expression of c-erbB-2, p53, Ki-67, Cyclin D1, Bcl-2, estrogen receptors (ER), and progesterone receptors (PR) in mammary Paget disease. METHODS: Archival tumor tissues from 14 patients diagnosed between 1990 and 1999 with Paget disease of the breast were analyzed for these molecular markers by using an automated immunohistochemical assay. Both the intraepidermal Paget cells and the underlying carcinoma were assessed for these markers. RESULTS: The majority of Paget cells were positive for c-erbB-2 (92.9%), Cyclin D1 (100%), and Ki-67 (85.7%), but very few were positive for Bcl-2 (14.3%). p53 was overexpressed in 42.9% of the cases, and only 28.6% were positive for ER and PR. The rate of expression of these biologic markers was similar in both the Paget cells and the underlying intraductal and/or ductal carcinoma cells. CONCLUSIONS: Tumors from patients with Paget disease of the breast were positive for c-erbB-2, Cyclin D1, and Ki-67, molecular markers commonly associated with more aggressive tumor behavior and poorer survival in breast cancer patients. Few of these tumors expressed Bcl-2 or ER and PR, which are generally associated with a better prognosis. Similar expression of these markers in both Paget cells and the underlying carcinoma supports the theory that these cells are the result of an intraepidermal spread of ductal carcinoma.

Paget disease of the breast: analysis of 41 patients.

The treatment for the patients with Paget disease of the breast is controversial. This review of its natural history, treatment approach, and clinical outcome will help to formulate treatment. Forty-one patients with a diagnosis of Paget disease of the breast were retrospectively reviewed at Providence Hospital & Medical Centers from 1980 to 1999. Ninety-eight percent of patients had underlying carcinoma (ductal carcinoma in situ and/or invasive ductal cancer). Patients with a palpable mass have a much higher incidence of invasive ductal cancer, positive lymph node, and a worse survival rate. The median length of follow-up was 42 months (range: 6--200 months). Twenty-seven percent of patients (11/41) had conservative operations, including 1 patient with a palpable mass; 10 patients with no palpable mass; and 3 patients with recurrence after conservative operation. Thirty-seven percent of patients received adjuvant therapy. Paget disease of the breast has very high incidence of underlying carcinoma (100% in a palpable mass, 96% in nonpalpable mass). Patients with a palpable mass have a worse survival than do patients with nonpalpable mass. Conservative operation should cautiously be selected even for patients with no palpable mass because of a higher recurrence rate.

The design of phenylglycine containing benzamidine carboxamides as potent and selective inhibitors of factor Xa.

Factor Xa, a critical serine protease in the blood coagulation cascade, has become a target for inhibition as a strategy for the invention of novel anti-thrombotic agents. Here we describe the development of phenylglycine containing benzamidine carboxamides as novel, potent and selective inhibitors of factor Xa.

DNA binding, solubility, and partitioning characteristics of extended lexitropsins.

Four new ligands that bind to the minor groove of DNA have been designed, synthesized, and evaluated by DNA footprinting. Two of the ligands are polyamides containing central regions with five or six N-methylpyrrole units, conferring hydrophobicity and good binding affinity but without retaining the correct spacing for hydrogen bonding in the base of the minor groove. The two remaining ligands have central regions which are head-to-head-linked polyamides, in which the linker is designed to improve the phasing of hydrogen bonding of the ligand with the floor of the minor groove. The highest affinity was obtained with the two polypyrroles without headgroup spacers, indicating that H-bond phasing is secondary in determining affinity compared to the major hydrophobic driving force. With a dimethylaminoalkyl group, representing a moiety with modest base strength, at both ends, water solubility is good and pH-partition theory predicts that penetration through lipid membranes will be enhanced, compared to strongly basic amidine analogues of the alkaloid precursors. All four compounds bind to DNA, with strong selectivity for AT sequences but some tolerance of GC base pairs and subtle individual preferences. The data show that very high affinities can be anticipated for future compounds in this series, but drug design must take account of overall physicochemical properties as well as the details of hydrogen bonding between ligands and the floor of the minor groove.

Carotid artery injuries and their management.

BACKGROUND: Major vascular injuries in the region of the neck are most frequently the result of penetrating trauma. Evaluation and management of patients with injury to Zone II of the neck remains highly controversial. Most studies involve small number of patients with a lack of standardization of the nature of the injury in reporting outcome. It is the purpose of this study to propose a grading scale for vascular injuries in the neck that would allow for more uniform reporting of such injuries. EXPERIMENTAL DESIGN: A retrospective review of all patients treated for penetrating trauma to the neck was performed and the subset of patients with major vascular injuries identified. Data from this group of patients are presented. SETTING: Level II urban trauma center. PATIENTS AND INTERVENTIONS: During the period July 1984 to June 1994, 107 patients were treated for penetrating neck trauma. Injuries to the major arteries of the neck were present in 18 of the 107 patients (16.8%). All injuries were graded on the developed scale. Management protocol was based on the grade of the injury. Grade 1 injuries were managed non-operatively with systemic anticoagulation and low molecular weight dextran. Grade 2 injuries were treated with primary repair. Injuries of Grades 3 and 4 were treated by primary repair or interposition graft. Exceptions were isolated injuries of the external carotid artery, which were treated by ligation alone. RESULTS: Of the 18 patients with carotid artery injuries, 2 had injuries of the external carotid artery, treated with ligation alone. The internal carotid artery was injured in 7 cases. An interposition saphenous vein/PTFE graft was used in all cases. In 9 cases the common carotid artery was injured. Repair was accomplished by a combination of either a primary repair or interposition graft. Overall mortality was 3/16 (16.6%). No new or worsening of neurologic deficit occurred in any patient. CONCLUSIONS: Carotid artery injuries occur in about 17% of patients with penetrating neck trauma. Data regarding management and prognosis in these patients are at best concflicting, in part, due to lack of a standardized classification system. The proposed grading scale is designed to overcome this problem.

Sentinel lymph node dissection for primary cutaneous melanoma: a community hospital's initial experience.

Management of the regional lymph nodes remains the most controversial aspect of treating patients with intermediate-thickness cutaneous melanoma. Prospective studies have failed to demonstrate a significant survival advantage for patients undergoing elective lymph node dissection. The sentinel lymph node dissection (SLND) technique has been proposed as a method of accurately identifying patients with occult metastases in whom a regional lymph node dissection would be indicated. The majority of studies evaluating this technique have come from academic centers, most with dedicated melanoma clinics. This report describes the initial experience with SLND at a community hospital. Fifteen patients with intermediate-thickness primary cutaneous melanoma underwent preoperative lymphoscintigraphy with 99Tc-sulfur colloid. In addition, intraoperative lymphatic mapping using intradermally injected isosulfan blue was performed. Dissection was guided by radioactivity levels (in counts per second) as measured by a hand-held gamma probe. The resected lymph node or nodes were evaluated for micrometastases using routine hematoxylin and eosin staining and immunohistochemistry with S-100 and HMB-45. All patients were followed clinically for any evidence of recurrence. A sentinel node(s) was identified on preoperative lymphoscintigraphy in all 15 patients (100%). A single sentinel node was identified in 11 of 15 (73%), two nodes in 3 (20%), and one node in 1 (6.7%). The hand-held gamma probe reading correlated well with the site marked the "hot spot" (600-15,320 cps for the hot spot versus 10-350 cps for background). The sentinel lymph node was successfully identified and resected in all 15 patients. Blue-stained lymphatics and/or lymph nodes were present in 8 of 15 (53%) cases. Histopathology was negative for evidence of occult micrometastases in all patients. At mean follow-up of 221 days, all 15 patients remain with no evidence of disease. The outcomes for mapping and harvesting the sentinel node at a community institution compare favorably with results at major academic institutions. SLND may therefore be offered to patients with intermediate-thickness cutaneous melanoma in the community hospital setting with regional lymph node dissection and adjuvant interferon alpha-2b as options for patients with nodal micrometastases.

Pancreatic lipase/colipase-mediated triacylglycerol hydrolysis is required for cholesterol transport from lipid emulsions to intestinal cells.

This study tested the hypothesis that dietary cholesterol uptake by intestinal cells is dependent on the structure and composition of the lipid carriers in the extracellular milieu. In in vivo experiments with female C57BL/6 mice, cholesterol absorption from phospholipid/triacylglycerol emulsions was significantly reduced by administration of tetrahydrolipstatin, an inhibitor of pancreatic lipase. This inhibitor had no effect on the absorption of cholesterol from phospholipid vesicles. The importance of pancreatic-lipase-mediated triacylglycerol hydrolysis for cholesterol transport from emulsions to intestinal cells was confirmed by in vitro experiments with rat IEC-6 intestinal cells. Cellular uptake of cholesterol from emulsions with a phospholipid/triacylglycerol molar ratio of <0.3 could be stimulated by pancreatic lipase/colipase hydrolysis of the core neutral lipids. However, pancreatic lipase/colipase was ineffective in hydrolysing triacylglycerols in emulsions with a phospholipid/triacylglycerol molar ratio of >0.3. Phospholipase A2-mediated hydrolysis of the surface phospholipids was necessary prior to triacylglycerol hydrolysis in these phospholipid-rich emulsions and to the stimulation of cholesterol transport from these particles to IEC-6 cells. The data also revealed that minimal triacylglycerol hydrolysis was sufficient to significantly increase cholesterol transport from lipid emulsions to the intestinal cells. Thus the products of triacylglycerol hydrolysis, namely monoacylglycerol and non-esterified fatty acids, are key determinants in mediating cholesterol transport from lipid emulsions to intestinal cells. Taken together, these results support the hypothesis that remodelling of the surface and core components of lipid carriers is necessary prior to absorption of dietary cholesterol from the gastrointestinal tract.

Advantage of surgery and adjuvant chemotherapy in the treatment of primary gastrointestinal lymphoma.

BACKGROUND: Surgery has been the mainstay of treatment for gastrointestinal (GI) lymphoma. The role of adjuvant chemotherapy to surgery has not been clearly elucidated. METHODS: The review covered 100 patients who were diagnosed with primary GI lymphoma and treated from 1980 to 1993 at Providence Hospital (Southfield, MI), and Hartford and St. Francis Hospitals (Hartford, CT) with a median follow-up of 5 years. Forty-two patients were treated with surgery alone; 31 patients with surgery and adjuvant chemotherapy; 23 patients with primary chemotherapy, and 4 patients received no treatment. RESULTS: The 5-year actuarial survival based on the above treatments calculated by life-table analysis were 57%, 76%, 58%, and 0%, respectively. This series showed that surgery with adjuvant chemotherapy significantly improved the 5-year actuarial survival of patients with primary GI Lymphoma and that primary chemotherapy showed comparable survival to surgery alone. There was no difference in prognosis when comparing patients with different stage, grade, or location of disease in the GI tract. CONCLUSIONS: We recommend surgery when feasible with adjuvant chemotherapy as the mainstay of treatment for primary GI lymphoma. However, if a patient presents with comorbid factors, primary chemotherapy offers an effective alternative.

PRO_SELECT: combining structure-based drug design and combinatorial chemistry for rapid lead discovery. 1. Technology.

This paper describes a novel methodology, PRO_SELECT, which combines elements of structure-based drug design and combinatorial chemistry to create a new paradigm for accelerated lead discovery. Starting with a synthetically accessible template positioned in the active site of the target of interest, PRO_SELECT employs database searching to generate lists of potential substituents for each substituent position on the template. These substituents are selected on the basis of their being able to couple to the template using known synthetic routes and their possession of the correct functionality to interact with specified residues in the active site. The lists of potential substituents are then screened computationally against the active site using rapid algorithms. An empirical scoring function, correlated to binding free energy, is used to rank the substituents at each position. The highest scoring substituents at each position can then be examined using a variety of techniques and a final selection is made. Combinatorial enumeration of the final lists generates a library of synthetically accessible molecules, which may then be prioritized for synthesis and assay. The results obtained using PRO_SELECT to design thrombin inhibitors are briefly discussed.

Immunisation of rainbow trout Oncorhynchus mykiss with a multiple antigen peptide system (MAPS).

To test the effectiveness of a multiple antigen peptide system (MAPS) as a method of vaccinating fish against peptides, rainbow trout were immunised with two MAPS containing the decapeptide GnRH. The first (MAPS 1) was homologous for GnRH, whereas the second (MAPS 2) was heterologous and contained alternating sequences of GnRH and a measles virus T cell epitope. Following vaccination with varying concentrations of the MAPS, serum antibody titres were monitored for 10 weeks. Only MAPS administered in adjuvant elicited an antibody response against GnRH. Whilst the kinetics of the responses mirrored those seen in sera from fish vaccinated against GnRH coupled to a carrier protein, the magnitude of the responses were significantly lower in sera from fish vaccinated with both MAPS. Interestingly, higher titres were seen against the MAPS than against GnRH in ELISA, possibly reflecting additional epitopes. The data are discussed with respect to the need to define T cell epitopes in fish, to allow the synthesis of more effective heterologous MAPS for future studies.

Recombinant human insulin-like growth factor I increases insulin sensitivity and improves glycemic control in type II diabetes.

Insulin resistance is a major factor in the pathophysiology of type II diabetes and a major impediment to successful therapy. The identification of treatments that specifically target insulin resistance could improve diabetes management significantly. Since IGFs exert insulin-like actions and increase insulin sensitivity when administered at supraphysiological doses, we determined the effect of 6 weeks of recombinant human IGF-I (rhIGF-I) administration on insulin resistance and glycemic control in obese insulin-resistant patients with type II diabetes. A total of 12 patients with type II diabetes were recruited for the study. Subcutaneous administration of rhIGF-I (100 micrograms/kg b.i.d.) significantly lowered blood glucose. Fructosamine declined from 369 to 299 mumol/l by 3 weeks of administration and then declined further to 271 at the end of 5 weeks. Glycosylated hemoglobin, which was 10.4% pretreatment, declined to 8.1% at the end of therapy. Mean 24-h blood glucose during a modal day was 14.71 +/- 4.5 mmol/l pretreatment and declined to 9.1 +/- 3.21 mmol/l by the end of treatment. These improvements in glycemia were associated with a decrease in serum insulin levels. Mean insulin concentrations declined from 108.0 to 57.0 pmol/l during the modal day measurements and from 97.2 to 72.0 pmol/l during the mixed-meal tolerance test. Changes in glycemia were accompanied by a marked increase in insulin sensitivity. The insulin sensitivity index (SI) calculated from a frequently sampled intravenous glucose tolerance test (FSIVGTT) after the method of Bergman et al. (Bergman RN, Finegold DT, Ader M: Assessment of insulin sensitivity in vivo. Endocr Rev 6:45-86, 1985) increased 3.4-fold. Furthermore, the improvement in glycemic control was accompanied by a change in body composition with a 2.1% loss in body fat as calculated by dual energy x-ray absorptiometry without change in total body weight. Significant side effects were present in some subjects, although nine subjects were able to complete at least 4.5 weeks of the protocol and six subjects completed the entire 6 weeks. Supraphysiological IGF-I concentrations were maintained throughout the study, increasing from 206 micrograms/l in the control period to 849 micrograms/l at the end of 6 weeks of rhIGF-I treatment. The increase in IGF-I levels was accompanied by a significant increase in IGF binding protein-2 levels, a slight reduction in IGF binding protein-3 levels, and an increase in levels of IGF binding protein-1. In summary, IGF-I significantly lowered blood glucose as reflected by short-term and long-term indexes of glycemic control and increased insulin sensitivity. It remains to be determined whether a dosage can be administered that avoids significant side effects and still achieves reasonable glycemic control.

Changes in insulin-like growth factor (IGF)-binding proteins after IGF-I injections in noninsulin-dependent diabetics.

Insulin-like growth factor-I (IGF-I) exerts insulin-like effects on fuel metabolism and suppresses insulin secretion in normal subjects. Unlike insulin, circulating IGF-I is bound to high affinity binding proteins (IGFBPs), which modulate IGF action. We have previously shown that IGF-I administration increases IGFBP-1 and -2 and reduces IGFBP-3 in normal subjects. To determine whether similar effects could be demonstrated in an insulin-resistant state, we administered recombinant human IGF-I for 4 days by sc injection to six obese type II diabetics and determined the effects on fasting concentrations of glucose, C-peptide, IGF-I, and IGFBPs. The changes that occurred in glucose C-peptide and IGFBP levels during oral glucose tolerance testing were also quantified. There was no significant decrease in the mean fasting serum glucose or C-peptide level despite a 7-fold increase in mean fasting IGF-I concentrations (P < 0.01). As expected, during oral glucose tolerance testing, the area under the curve of C-peptide was suppressed after an injection of IGF-I (P < 0.05), but the area under the glucose curve did not change significantly. Mean fasting daily IGFBP-1 and -2 rose 2-fold (P < 0.05) and 1.9-fold (P < 0.05), respectively, whereas IGFBP-3 fell by 16% (P < 0.01) after 4 days of injections. IGFBP-1 was suppressed by 32% after oral glucose alone, whereas an injection of IGF-I plus oral glucose were associated with a more marked fall of 53% (despite suppression of C-peptide). In contrast, mean IGFBP-2 concentrations rose by 40% (P < 0.05) after IGF-I and oral glucose, but there was no change in response to oral glucose alone. These changes in IGFBP-1, -2, and -3 could alter the distribution of IGF-I among the various IGFBPs in the circulation. They may also prove to be a marker of metabolic responsiveness to IGF-I. In a substrate-sufficient state, e.g. after oral glucose, IGFBP-1 and -2 show opposite acute responses to IGF-I, and IGF-I has an apparent acute insulin-like effect on IGFBP-1 concentrations that differs from its longer term effect.

Cyclic peptides as selective tachykinin antagonists.

Twenty homodetic cyclic peptides based on the C-terminal sequence of substance P were prepared (Table I) by a combination of solid-phase techniques and cyclizations using azide coupling procedures. Incorporation of dipeptide mimics based on substituted gamma-lactams were used in some cases to restrict their conformational mobility. Five of these cyclic peptides were shown to have high tachykinin antagonist activity (pA2 > 6) at NK-2 receptors (rat vas deferens). The two most potent of this series, XVII, cyclo(Gln-Trp-Phe-Gly-Leu-Met) (pA2 = 8.1), and I cyclo(Gln-Trp-Phe(R)Gly[ANC-2]Leu-Met) (pA2 = 6.7), were selective for NK-2 receptors compared with the other tachykinin receptors (Table II).

Determination of the pharmacokinetic profiles of insulin-like growth factor binding proteins-1 and -2 in rats.

The insulin-like growth factor binding proteins (IGFBPs) are present in serum and alter the half-life of IGF-I and II in the vascular compartment. Because both IGFBP-1 and 2 have been proposed as regulators of IGF transport, we directly determined their distribution and elimination characteristics in rats. 125I-IGFBP-1 and 2 were injected into anesthetized normal rats. Multiple blood samples were drawn over time and the trichloroacetic acid precipitable radioactivity used to determine their pharmacokinetic profiles. The mean residence time for IGFBP-1 was 129 +/- 31 min and for IGFBP-2 116 +/- 24 min. The volume of distribution at steady state was 300 +/- 87 ml/kg for IGFBP-1 and 242 +/- 32 ml/kg for IGFBP-2. The elimination half-life was 120 +/- 26 min for IGFBP-1 and 144 +/- 32 for IGFBP-2. The results show that two separate methods of analysis give equivalent results for estimation of half-lives of these forms of IGFBPs and that their half-lives are substantially greater than that reported for free IGF-I, but less than that reported for the 150-kilodalton IGF complex. The findings suggest that these proteins equilibrate with extravascular compartments and may have a role in modulating transvascular transport of IGF-I and II.

Effects of recombinant insulin-like growth factor-I (IGF-I) and growth hormone on serum IGF-binding proteins in calorically restricted adults.

To determine the effects of exogenous insulin-like growth factor-I (IGF-I) and GH on IGF-binding proteins (IGFBP)-1, -2, and -3, six healthy nonobese adult volunteers underwent two 2-week periods of diet restriction (20 Cal/kg.day), and during the last 6 days of the first period received either IGF-I (12 micrograms/kg.h by iv infusion over 16 h) or GH (0.05 mg/kg.day by sc injection). During the second 2-week study period, the alternate hormone was given. IGFBP-1 and -2 concentrations were determined by specific RIA, and changes in IGFBP-3 were assessed by ligand blotting. Free IGF-I concentrations were measured by size-exclusion high pressure liquid chromatography, followed by RIA. Diet restriction alone did not affect either IGFBP-1 or -2 significantly. IGF-I treatment increased IGFBP-1 from 78 +/- 46 ng/mL (mean pretreatment) to 137 +/- 64 ng/mL (P less than 0.001; mean for the last 4 days of IGF-I). IGF-I also caused an increase in IGFBP-2 from 315 +/- 136 to 675 +/- 304 ng/mL (P less than 0.001). GH injections caused a modest decline in IGFBP-1 concentrations but had no effect on IGFBP-2 concentrations. By ligand blotting, both IGF-I and GH caused a modest increase in IGFBP-3 band intensity. In three subjects diet restriction alone caused a small decrease in IGFBP-3 hand intensity, and this was reversed by hormone treatment. Free IGF-I concentrations in serum were increased from 1.6% to 4.4% of the total IGF-I during IGF-I infusions. GH injections caused a smaller increase in free IGF-I concentrations. The results show significant increases in IGFBP-1 and -2 during IGF-I infusion. The change in IGFBP-3, while significant, is quantitatively less than that in experimental animals that have been given IGF-I while undergoing dietary restriction. The net effect of the changes in these three forms of IGFBPs is not sufficient to maintain a normal IGF-I-binding capacity in serum, because free IGF-I levels were increased disproportionately during the IGF-I infusions. Because hypoglycemia was noted in these subjects despite insulin suppression, these alterations in IGFBPs might have changed the tissue bioavailability of IGF-I and facilitated its hypoglycemic effects.

A critical look at abdominal lipectomy following morbid obesity surgery.

This article reviews a series of 26 consecutive nonaesthetic post-morbid-obesity weight loss patients undergoing abdominal lipectomy. Patient satisfaction was assessed by a questionnaire. All patients obtained symptomatic relief but surprisingly most had expected to look better following surgery, indicating the importance of discussing this aspect preoperatively. Technical modifications to remedy some of these problems are discussed.