Sphincter-saving surgery in patients with rectal cancer treated by radiotherapy and transanal endoscopic microsurgery: 10 years' experience.

BACKGROUND/AIMS: Transanal endoscopic microsurgery (TEM) is a technique which allows minimally invasive full-thickness local excision of rectal tumours with perirectal fat dissection. METHODS: Our study examined a group of 137 selected patients with rectal cancer treated by TEM excision combined with preoperative radiotherapy. The definitive histology was as follows: 37 patients with pT1 stage rectal cancer (27%), 59 with pT2 (43%) and 23 with pT3 (17%). In 18 (13%) patients who underwent a full dose of radiotherapy and TEM, the pathologist did not find cancer cells in the specimen (pT0). RESULTS: Eleven (8%) patients developed minor complications, whereas three (2%) developed major complications. The perioperative mortality was nil. At the mean follow-up of 46 months (range 6-115 months), we observed seven (5%) local recurrences. Of those, three patients died from systemic spread of the disease at follow-up. The disease-free survival rate in T0 and T1 patients was 100%. The disease-free survival rates in T2 and T3 patients were 81 and 59%, respectively, at a mean follow-up of 46 months. CONCLUSIONS: The application of preoperative radiotherapy and TEM in the treatment of rectal tumours appears feasible, safe and effective in the present study, with optimal preservation of anal sphincter function.

Type a syndrome of insulin resistance: anterior chamber anomalies of the eye and effects of insulin-like growth factor-I on the retina.

BACKGROUND: The purpose of this work was to describe the anterior chamber and iris anomalies as well as to evaluate the effects of recombinant human insulin-like growth factor-I (rhIGF-I) on the retinal vessels in 2 diabetic patients with type A syndrome of insulin resistance, a rare condition associated with acanthosis nigricans. METHODS: Ophthalmologic examinations, including photographs and fluorescein angiograms, were performed before, and 2 and 4 weeks after starting subcutaneous rhIGF-I treatment, and 3 months after withdrawal of rhIGF-I treatment. RESULTS: Both patients had goniodysgenesis with mild elevation of the intraocular pressure. Before and after 2 weeks of treatment with rhIGF-I, the fundus and the fluorescein angiograms were mainly normal. After 4 weeks of rhIGF-I treatment both patients' retinas revealed leakage of fluorescein. Three (case 1) and 4 months (case 2) after withdrawal of rhIGF-I, the fundus of all four eyes were again without leakage. CONCLUSIONS: The anterior chamber anomalies found in these patients may be part of the type A syndrome of insulin resistance and could alert clinicians that these patients might not have the usual type of diabetes. Moreover, the data show that exogenous rhIGF-I administration in patients with type A syndrome of insulin resistance alters the permeability of the superficial layer of retinal capillaries which is comparable to the earliest angiographic changes in childhood diabetic retinopathy. Whether this is a direct effect of rhIGF-I, as suggested by experiments in an animal model, or an indirect effect due to the near-normalization of the glucose levels by rhIGF-I warrants further investigations. Finally, this work points to an important caveat regarding the therapeutic use of rhIGF-I in this patient population.

Laparoscopic adrenalectomy by the anterior transperitoneal approach: results of 108 operations in unselected cases.

BACKGROUND: The feasibility, safety, and results of 108 laparoscopic anterior transperitoneal adrenalectomies (six bilateral) were evaluated in a series of 105 patients. Three patients with a preoperative diagnosis of primary adrenal carcinoma were excluded from the study. METHODS: A total of 102 patients were included in the study based on exhaustive endocrinological and imaging assessment. Twenty-nine patients with nonsecreting adenoma, 34 with aldosterone-producing adenoma, 27 with cortisol-producing adenoma (five bilateral), 13 with pheochromocytoma (one bilateral), two with androgen-secreting adenoma, and three with metastases were considered eligible for adrenalectomy. Lesion size ranged from 3.5 to 12 cm. Concurrent surgical procedures were performed in 10 patients (9.8%). RESULTS: One (0.9%) intraoperative complication, a colon tear in a bilateral adrenalectomy, required conversion. There were two (1.9%) postoperative complications: one patient with thrombocytopenia developed hemoperitoneum and required a second laparoscopic procedure, and an intraabdominal abscess was treated medically. Mean postoperative hospital stay was 2.5 days (range, 1-7 days). Postoperative mortality was 0.9%; the patient with the colon tear died of sepsis 60 days after the operation. At a mean follow-up of 30 months (range, 1-62), normalization or improvement in hormone levels was observed in all patients with secreting adenomas, and significant improvement or cure was achieved in all patients with hypertension. CONCLUSION: Patients with secreting and nonsecreting adrenal lesions can be treated safety and effectively by laparoscopy with the anterior transperitoneal approach.

Local excision of rectal cancer by transanal endoscopic microsurgery (TEM) combined with radiotherapy: new concept of therapeutic approach.

Transanal endoscopic microsurgery (TEM), associated with preoperative radiotherapy in selected groups, allows minimally invasive full thickness local excision of rectal tumors with perirectal fat dissection. In our experience, 95 patients with extraperitoneal rectal carcinoma underwent TEM resection for T1 (21 cases), T2 (48 cases) and T3 (15 cases) lesions. In eleven patients the pathologist did not find cancer cells in the specimen (pT0) after full dose of radiotherapy and TEM. The postoperative results were as follows: 11 minor complications (11.6%), 7 leaking sutures, 3 stool incontinence and 1 rectal haemorrhage, that resolved with medical therapy and two major complications (2.1%), one rectovaginal fistula that required reoperation and one rectourethral fistula treated by conservative therapy. No perioperative mortality was observed. Mean follow up was 40 months (range 2-96 months) with 7 (7.4%) local recurrences. Of those, 5 patients were successfully retreated and 2 high risk patients underwent postoperative radiotherapy. The overall survival in T0 and T1 patients was 100%. The overall survival in T2 and T3 patients was 81% and 62.1% respectively. This study reports the application of TEM combined with radiotherapy in the treatment of rectal cancer in selected patients. This approach is feasible, safe, and appears to be effective at the present follow up, with preservation of normal sphincter function.

[Echography in minimally invasive surgery]. / L'ecografia in chirurgia mininvasiva.

Thanks to the great development of laparoscopic surgery and his continuous technical evolution, echography plays more and more important role in the pre- and intraoperative diagnosis. In the hepato-pancreatic pathology the use of the laparoscopic echography reduces clearly the role of laparotomic exploration. In laparoscopic surgery of rectal-colon, the echography is more specific and sensitive in compared with pre-operative MR and CT to individualize liver metastasis, to locate them. This allows the treatment of such lesions through the cryosurgery. In pancreatic lesions such method plays a non releasable role in tumors staging, giving essential elements to the surgeon to operate and for a better definition of operative strategy. Also in the adrenal masses surgery, laparoscopic echography reveals very useful especially in the anatomical structures identification (i.e. renal vein and entrance of the left adrenal vein) in the patients already operated or obese. In the preoperative study of rectal tumors the use of rotating and transrectal probes allows to define the degree of infiltration of the lesion and to perform a mini-invasive treatment through endoscopic transanal microsurgery with the radiochemotherapy. Thus echography in mini-invasive surgery has an unreplaceable role both in diagnosis as in evaluation of the parameter of therapeutical approach.

Beneficial metabolic effects of insulin-like growth factor I in patients with severe insulin-resistant diabetes type A.

Severe insulin resistance type A is due to mutations in the insulin receptor gene and is characterized by glucose intolerance or diabetes mellitus, despite extreme hyperinsulinemia, virilization and acanthosis nigricans. At present, there is no therapy for this condition. Recently, we showed that glucose levels in three such patients are promptly lowered by an i.v. bolus of recombinant human insulin-like growth factor I (rhIGF-I). In the present study, we investigated two of these rare patients again and determined fasting and postprandial glucose, insulin, C-peptide, proinsulin and lipid levels during five control, five treatment and three wash-out days while on a constant diet. Treatment consisted of 2 x 150 micrograms rhIGF-I/kg sc per day, which elevated total IGF-I levels 4.5-fold above the control. Fasting glucose levels (days 1-5) in the two patients were 9.6 +/- 1.3 and 9.2 +/- 1.2 mmol/l, respectively, and fell to 4.4 +/- 0.4 and 5.1 +/- 0.5 mmol/l on treatment days 8-10. Fasting insulin (2950 +/- 450 and 690 +/- 125 pmol/l), C-peptide (2217 +/- 183 and 1317 +/- 235 pmol/l) and proinsulin control levels (125 +/- 35 and 66 +/- 0 pmol/l) also decreased by approximately 65% during rhIGH-I treatment, as did the respective postprandial levels. Lipid levels hardly changed at all. In conclusion, IGF-I appears to correct partially some metabolic sequelae of severe insulin resistance and may, hence, be used as a new therapeutic agent.

Metabolic and therapeutic effects of insulin-like growth factor I.

The administration of rhIGF-I in appropriate doses leads to a decrease of insulin and growth hormone secretion and to an increase of insulin sensitivity. In type 2 diabetic patients, IGF-I improves glycemic profiles. In normal subjects, IGF-I increases energy expenditure and lipid oxidation and has a protein-sparing effect. Total and VLDL-triglycerides as well as LDL-cholesterol are decreased by IGF-I administration. This metabolic profile of IGF-I allows speculation on its possible usefulness in conditions of relative insulin resistance often associated with increased cardiovascular morbidity and mortality.

The effects of insulin-like growth factor-1 on plasminogen activator inhibitor-1 synthesis and secretion: results from in vitro and in vivo studies.

In vitro studies have shown that insulin and IGF-1 releases the fibrinolytic inhibitor plasminogen activator inhibitor-1 (PAI-1) from cells of hepatic origin. To investigate the effects of IGF-1 on fibrinolysis: 1) cultured hepatoma cells were grown in the presence of IGF-1 and media collected for secreted PAI-1 and cells probed for PAI-1 mRNA, 2) 8 hypopituitary patients were treated with recombinant human growth hormone (rhGH) and 3) 5 type 2 diabetic patients were treated with recombinant human IGF-1 (rhIGF-1). Treatment of Hep G2 cells with IGF-1 (1000 ng/ml) increased secretion of PAI-1 from a median value of 80 ng/10(6) cells (range 21-91) to 144 ng/10(6) cells (range 128-169) after 24 h (p < 0.01). Synthesis of PAI-1 mRNA increased in a similar fashion. Treatment of hypopituitary patients with rhGH led to an increase in circulating IGF-1 from a mean value of 166 (range 41-324) ng/ml at baseline to 322 (77-575) ng/ml at 4 weeks and 259 (104-533) ng/ml after 8 weeks (p < 0.02). Despite this, no changes in circulating PAI-1 or fibrinolysis occurred. Type II diabetic patients treated with rhIGF-1 showed an increase in circulating IGF-1 from a mean value of 120 ng/ml (range 109-196), at baseline to 823 ng/ml (585-894) after 5 days. This also was not associated with changes in circulating PAI-1 or in fibrinolysis. The results confirm that IGF-1 induces the synthesis of PAI-1 in Hep G2 cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Improvement of lipid profile in type 2 (non-insulin-dependent) diabetes mellitus by insulin-like growth factor I.

Type 2 (non-insulin-dependent) diabetes mellitus is associated with increased glucose, insulin, total and VLDL-triglyceride, and often total and LDL-cholesterol levels which promote vascular disease. Recombinant human insulin-like growth factor-I which mimics many effects of insulin, decreased insulin, total and VLDL-triglyceride, and total and LDL-cholesterol levels in healthy man as well as glucose and insulin levels in Type 2 diabetic patients. We, therefore, investigated total and fractionated triglyceride and cholesterol levels, lipoprotein(a), non-esterified fatty acid, and apolipoprotein levels in eight Type 2 diabetic patients during five control, five treatment, and three wash-out days. They received a constant diet throughout and daily 2 x 120 micrograms insulin-like growth factor-I/kg s.c. during the treatment period. Fasting total and VLDL-triglyceride, total and LDL-cholesterol control levels were (mean +/- SD) 3.1 +/- 2.6, 1.3 +/- 1.0, 6.3 +/- 1.3, and 4.5 +/- 1.1 mmol/l and decreased to 1.6 +/- 0.8, 0.6 +/- 0.4, 5.0 +/- 1.0, and 3.5 +/- 1.1 mmol/l, respectively, on the last treatment day (p < 0.01). During therapy, fasting lipoprotein(a) levels and the postprandial area under the triglyceride curve decreased by 48 +/- 22 and 32 +/- 18% of control (p < 0.01), respectively. In conclusion, insulin-like growth factor-I lowered lipid levels in Type 2 diabetic patients directly or indirectly or both because of decreased glucose and insulin levels. Long-term trials would be of interest with respect to the cardiovascular risk in Type 2 diabetes and patients with hyperlipidaemia.

Insulin-like growth factor-I improves glucose and lipid metabolism in type 2 diabetes mellitus.

Hyperglycemia, hyperinsulinemia, and insulin resistance cause vascular disease in type 2 diabetes mellitus. Dietary treatment alone often fails and oral drugs or insulin enhance hyperinsulinemia. In previous studies, an intravenous bolus of recombinant human insulin-like growth factor-I (rhIGF-I) caused normoglycemia in insulin-resistant diabetics whereas rhIGF-I infusions lowered insulin and lipid levels in healthy humans, suggesting that rhIGF-I is effective in insulin-resistant states. Thus, eight type 2 diabetics on a diet received on five treatment days subcutaneous rhIGF-I (2 x 120 micrograms/kg) after five control days. Fasting and postprandial glucose, insulin, C-peptide, proinsulin, glucagon, triglyceride, insulin-like growth factor-I and -II, and growth hormone levels were determined. RhIGF-I administration increased total IGF-I serum levels 5.3-fold above control. During the control period mean (+/- SD) fasting glucose, insulin, C-peptide, and total triglyceride levels were 11.0 +/- 4.3 mmol/liter, 108 +/- 50 pmol/liter, 793 +/- 250 pmol/liter, and 3.1 +/- 2.7 mmol/liter, respectively, and decreased during treatment to a nadir of 6.6 +/- 2.5 mmol/liter, 47 +/- 18 pmol/liter, 311 +/- 165 pmol/liter, and 1.6 +/- 0.8 mmol/liter (P < 0.01), respectively. Postprandial areas under the glucose, insulin, and C-peptide curve decreased to 77 +/- 13 (P < 0.02), 52 +/- 11, and 60 +/- 9% (P < 0.01) of control, respectively. RhIGF-I decreased the proinsulin/insulin ratio whereas glucagon levels remained unchanged. The magnitude of the effects of rhIGF-I correlated with the respective control levels. Since rhIGF-I appears to improve insulin sensitivity directly and/or indirectly, it may become an interesting tool in type 2 diabetes and other states associated with insulin resistance.

Effects of insulin-like growth factor-I on glucose tolerance, insulin levels, and insulin secretion.

Insulin-like growth factor-I (IGF-I) and insulin interact with related receptors to lower plasma glucose and to exert mitogenic effects. Recombinant human IGF-I (rhIGF-I) was recently shown to decrease serum levels of insulin and C-peptide in fasted normal subjects without affecting plasma glucose levels. In this study we have investigated in six healthy volunteers the responses of glucose, insulin, and C-peptide levels to intravenous rhIGF-I infusions (7 and 14 micrograms/kg.h) during standard oral glucose tolerance tests (oGTT) and meal tolerance tests (MTT), respectively. Glucose tolerance remained unchanged during the rhIGF-I infusions in the face of lowered insulin and C-peptide levels. The decreased insulin/glucose-ratio presumably is caused by an enhanced tissue sensitivity to insulin. The lowered area under the insulin curve during oGTT and MTT as a result of the administration of rhIGF-I were related to the fasting insulin levels during saline infusion (oGTT: r = 0.825, P less than 0.05; MTT: r = 0.895, P less than 0.02). RhIGF-I, however, did not alter the ratio between C-peptide and insulin, suggesting that the metabolic clearance of endogenous insulin remained unchanged. In conclusion, rhIGF-I increased glucose disposal and directly suppressed insulin secretion. RhIGF-I probably increased insulin sensitivity as a result of decreased insulin levels and suppressed growth hormone secretion. RhIGF-I, therefore, may be therapeutically useful in insulin resistance of type 2 diabetes, obesity, and hyperlipidemia.

Recombinant human insulin-like growth factor I (rhIGF I) reduces hyperglycaemia in patients with extreme insulin resistance.

The syndrome of type A insulin resistance is encountered in young women and is characterized by glucose intolerance or frank diabetes mellitus, endogenous hyperinsulinism, insensitivity to insulin administration, acanthosis nigricans and virilization. The insulin resistance is due to reduced cellular insulin binding because of a lack of or defective binding sites and/or because the interaction with the tyrosine kinase of the beta-subunit is hindered. This study was undertaken to find out whether hyperglycaemia in these patients may be influenced by the administration of recombinant human insulin-like growth factor I which exerts insulin-like effects through the insulin receptor as well as the type 1 insulin-like growth factor I receptor. Recombinant human insulin-like growth factor I was intravenously administered in two subsequent doses of 100 micrograms/kg body weight to three women with type A insulin resistance. An immediate but slow fall of blood glucose was observed. The glucose disappearance rate was 28.0 mumol/min, i.e. considerably lower than that seen in healthy subjects. The markedly elevated insulin and C-peptide levels fell in a parallel manner to blood glucose but not to normal levels. The results show that recombinant human insulin-like growth factor I, presumably by reacting with the type 1 insulin-like growth factor receptor, can normalize serum glucose levels in patients with severe insulin resistance at least for several hours. We suggest that the potential or recombinant human insulin-like growth factor I to control hyperglycaemia in type A insulin resistant patients should be explored in more depth.

[Advantages and drawbacks of human insulin]. / Vor- und Nachteile von Humaninsulin.

Insulin (I) preparations used formerly contained a large number of protein contaminants which are thought to be immunogenic and, hence, caused lipodystrophy, I-allergy and sometimes antibody-mediated I-resistance in many patients. Monocomponent (MC)-I and human I (HI) are virtually free of these peptides and are, therefore, very rarely accompanied by the above mentioned immunologic side effects. In this respect, however, HI offers only little advantage over MC-I although HI is the least immunogenic I. On the other hand, the formation of antibody to I in the diabetic mother is an important determinant of fetal outcome. And since children from diabetic mothers treated with HI are less frequently macrosomic, the use of HI is strongly recommended in women with diabetes before and during their childbearing years. Neutral HI action is somewhat shorter, although clinically not to a relevant extent and, furthermore, metabolic control is not improved by using HI compared wtih MC-I. These findings have been regarded as disadvantages of HI, together with the fact that about 20% of HI-treated patients experience a change of hypoglycemia symptoms during the course of their illness. While autonomic symptoms become weaker or disappear, patients have to react to neuroglycogenic symptoms which normally remain constant. However, the incidence of hypoglycemic events does not change during treatment with HI. Several reasons for this change of symptoms are discussed, such as long duration of diabetes, intensified therapy with near-normoglycemia, development of autonomic neuropathy, alcoholic beverages, and often insufficient instruction of patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasmodium berghei: gametocyte production, DNA content, and chromosome-size polymorphisms during asexual multiplication in vivo.

In this study the DNA content and the karyotype of clones of Plasmodium berghei, which differed in the capability to produce gametocytes, were determined. The DNA content per haploid genome was established by cytofluorometric methods after staining of the haploid merozoites with DNA-specific fluorescent dyes. Field inversion gel electrophoresis was used to establish the number and size of the chromosomes. Parasites of a high gametocyte producer clone (original HP) and a low producer clone (original LP) contained 13 to 14 chromosomes in the size range of 0.5-3.8 megabase. In four independent experiments parasites of the original HP clone were maintained in mice and were mechanically transmitted for prolonged periods of time (up to 90 weeks). During the transmission period the capability to produce gametocytes decreased in all four lines. After mosquito transmission of parasites from these low producer lines, the gametocyte production returned to the level of the original HP clone. The total DNA content per haploid genome of low producer parasites was not significantly different from that of HP parasites. During prolonged periods of asexual multiplication of the HP clone in vivo, changes in the relative size of several chromosomes were detected. Mosquito transmission of the original HP clone did not result in a change of the karyotype. However, novel karyotypes were readily observed after mosquito transmission of parasites of the low producer lines. The decrease of the capability to produce gametocytes did not necessarily involve detectable changes in DNA content or in karyotype.

Insulin-like growth factors in the Göttinger miniature-pig.

IGF I was determined by a radioimmunoassay and IGF II by a radioreceptorassay in 20 Göttinger miniature (mini)-pigs and 13 domestic pigs of different weight and age. Immunoreactive IGF I serum levels of mini-pigs were similar to those of domestic pigs in corresponding age-classes (150-250 and 100-270 micrograms/l, respectively). No differences were detectable between receptor-reactive IGF II serum levels in mini-pigs (150-200 micrograms/l) and domestic pigs (110-270 micrograms/l) nor did the biological insulin-like activities (measured in the rat fat cell assay) differ in mini- and domestic pigs (81-100 and 71-98 mU insulin/l, respectively). IGF I and IGF II decreased drastically after hypophysectomy in one of the mini-pigs. Intravenous bolus injections of 30 micrograms/kg of recombinant human IGF I in 4 mini-pigs caused a similar degree of hypoglycemia (nadir of blood glucose 1.33 +/- 0.61 mmol/l) as 0.15 IU insulin/kg, followed by a sharp growth hormone peak. We conclude that the marked difference between mini- and domestic pigs regarding body size is unrelated to serum levels of IGF I and II, a lack of response of tissues to IGF I or a reduced growth hormone secretory capacity in the mini-pig.

Re-examination of earlier work on repetitive DNA and mosquito infectivity in rodent malaria.

Previous results, relating mosquito infectivity to percentage of repetitive DNA in the genome of Plasmodia, are re-examined in the light of the finding that a parasite line used in the previous studies and classified as Plasmodium berghei NK65, was a mixed infection, where the major component appeared to be Plasmodium yoelii. This conclusion was reached through cloning and isoenzyme typing of different clones. Isoenzyme typing alone is not sufficiently sensitive to reveal contamination amounting to less than 20% in a mixture. Attention is drawn to the risk inherent in work with uncloned lines, where the proportions of species or sub-species present may vary according to line history and gametocyte viability.