Management of premature ejaculation: a clinical guideline from the Italian Society of Andrology and Sexual Medicine (SIAMS).

Premature ejaculation (PE) is the most prevalent male sexual dysfunction, and the most recently defined. PE is often mistakenly considered a purely psychosexological symptom by patients: the lacking awareness in regards to the pathophysiology and treatments often lead to resignation from the patients' side, making PE the most underdiagnosed sexual complaint. However, an ever-growing body of evidence supporting several organic factors has been developed in the last decades and several definitions have been suggested to encompass all defining features of PE. In the present document by the Italian Society of Andrology and Sexual Medicine (SIAMS), we propose 33 recommendations concerning the definition, pathophysiology, treatment and management of PE aimed to improve patient care. These evidence-based clinical guidelines provide the necessary up-to-date guidance in the context of PE secondary to organic and psychosexological conditions, such as prostate inflammation, endocrine disorders, and other sexual dysfunctions, and suggest how to associate pharmacotherapies and cognitive-behavioral therapy in a couple-centered approach. New therapeutic options, as well as combination and off-label treatments, are also described.

Suppression of the high endogenous levels of plasma FSH in infertile men are associated with improved Sertoli cell function as reflected by elevated levels of plasma inhibin B.

BACKGROUND: In vitro continuous stimulation of Sertoli cells with FSH leads to a desensitization of these cells to FSH action. To evaluate the presence of a desensitization of FSH receptor on Sertoli cells in vivo, we performed a controlled clinical study in 97 men affected by severe oligozoospermia. METHODS: On the basis of FSH and inhibin B plasma concentrations, these subjects were divided into three groups: group A, 33 subjects with high FSH and low inhibin B plasma levels; group B, 32 subjects with high FSH plasma levels and inhibin B concentrations at the lower limit of the normal range; and group C, 32 subjects with normal FSH and inhibin B plasma levels. Patients with high FSH plasma levels (groups A and B) were prospectively randomized into two subgroups, called A1, A2, B1 and B2. Patients of groups A1 and B1 were treated with a GnRH agonist, leuprolide acetate, to induce a hypogonadotrophic state and then were treated with recombinant human FSH (r-hFSH; 100 IU/day) and hCG (2000 IU/twice a week) for 2 months. Subjects of groups A2, B2 and C were treated only with r-hFSH for the same period. RESULTS: In patients of group A1, inhibin B remained unmodified during the whole period of study, whereas in subjects of group B1, we observed a significant reduction of this hormone during the hypogonadotrophic period and then an increase of inhibin B plasma levels that were higher that those observed before therapy. In patients of groups A2 and B2, FSH treatment did not induce a significant increase in inhibin B concentrations. In patients of group C, FSH induced a significant increase in inhibin B plasma levels. CONCLUSIONS: In infertile men, suppression of the high endogenous levels of plasma FSH associated with much lower exogenous FSH levels is able to evoke higher inhibin B production, which may indicate improved Sertoli cell function and the possibility that this could have a positive effect on spermatogenesis.

[Needle aspiration testicular cytology as diagnostic parameter in the assessment with varicocele]. / La citologia testicolare per agoaspirazione come parametro diagnostico nella valutazione del soggetto affetto da varicocele.

OBJECTIVE: Varicocele is considered the most common cause of male infertility. The pathogenesis of the spermatogenetic impairment in this disease is not completely understood and the seminal patterns of patients with varicocele are different. Testicular fine-needle aspiration cytology (FNAC) in infertile men allows us to obtain many information about the type and the degree of alteration of the seminiferous tubule. MATERIALS AND METHODS: In this study, 200 infertile men with varicocele were evaluated for seminal parameters, FSH, LH and testosterone plasma concentrations. Testicular pattern was analyzed by bilateral FNAC. All patients suffered of infertility for at least two years and varicocele was the sole infertility-related pathology. According to the tubular patterns, we divided the patients into five groups, and we observed that the different tubular alterations could be present in patients with similar FSH levels and similar sperm count. Then, to verify the role of tubular pattern as prognostic factor for the correction of varicocele, we studied 70 men, performing seminal analysis and hormonal evaluation six months after sclerotherapy. RESULTS: We found an increasing in sperm count and in other seminal parameters after the sclerotherapy (motility, normal morphology...) only in patients with maturative alteration at spermatid level. This alteration of spermiogenesis seems to be reversible after sclerotherapy. CONCLUSION: In the light of these results the testicular FNAC gives important prognostic parameters in the selection of patients affected by varicocele for sclerotherapy.

Store-operated calcium influx and stimulation of steroidogenesis in rat Leydig cells: role of Ca(2+)-activated K(+) channels.

This study evaluates the role of internal calcium store depletion in the activation of ionic fluxes and steroidogenesis in adult rat Leydig cells. Thapsigargin and cyclopiazonic acid, two inhibitors of Ca(2+)-adenosine triphosphatase of internal Ca(2+) stores induced a dose-dependent rise in intracellular Ca(2+) concentrations following kinetics that would not be expected if the calcium rise was dependent only on internal calcium store depletion, but it was in keeping with the presence of calcium influx from the external medium. In fact, chelation of external calcium with EGTA during the plateau phase reduced the intracellular calcium concentration to basal levels. When added in calcium-free medium, thapsigargin and cyclopiazonic acid still induced a rise in the intracellular calcium concentration that was transient, and when calcium was added back to the medium, a rapid and sustained intracellular calcium increase was observed. Thapsigargin and cyclopiazonic acid induced a dose-dependent rise in testosterone secretion in the presence and absence of calcium in the external medium, although in calcium-free medium this stimulatory effect was lower. Leydig cell plasma membrane potential monitoring demonstrated that thapsigargin and cyclopiazonic acid induced first a rapid hyperpolarization, followed by a sustained depolarization phase that was reversed by the addition of the calcium-chelating agent EGTA. In the absence of calcium in the external medium the first phase of hyperpolarization was still present, but it was not followed by plasma membrane depolarization but by the slow return of plasma membrane potential to resting levels. The readdition of calcium to the external medium induced the rapid plasma membrane depolarization. Plasma membrane hyperpolarization was completely abolished by Leydig cell preincubation with the K(+) channel blockers tetraethylammonium and charybdotoxin. Leydig cell preincubation with K(+) channel inhibitors reduced the thapsigargin-stimulated Ca(2+) influx from the external medium and testosterone secretion. These results suggest that internal Ca(2+) stores depletion in rat Leydig cells induces a rise in intracellular Ca(2+), determining important plasma membrane potential variations that influence testosterone secretion.

Extracellular ATP stimulates estradiol secretion in rat Sertoli cells in vitro: modulation by external sodium.

In this study, we examined the effects of extracellular ATP (ATPe) on [Ca(2+)](i), [Na(+)](i), plasma membrane potential changes and estradiol secretion in rat Sertoli cells. ATPe caused a rapid rise of [Ca(2+)](i) with an initial spike followed by a long lasting plateau. The first rapid spike was dependent on the release of Ca(2+) from internal stores as it also occurred in Ca(2+)-free medium while the long lasting plateau phase was dependent on Ca(2+) influx from the external medium. ATPe stimulated a rapid plasma membrane depolarization that was dependent on an influx of Na(+) from the external medium as demonstrated by plasma membrane potential monitoring in Na(+)-free medium and by [Na(+)](i) measurement with the Na(+)-sensitive fluorescent dye SBFI. ATPe stimulated estradiol secretion in a dose dependent manner and was fully dependent on the presence of Na(+) in the external medium while the presence of Ca(2+) was not necessary. Among the different nucleotides tested, only ATP, ATP-5'-[gamma-thio]triphosphate, UTP, alpha,beta-methylene-ATP were effective in stimulating estradiol secretion. These results demonstrate that rat Sertoli cells possess P2-purinergic receptors belonging to the P2X and P2Y subfamily which activation induces [Ca(2+)](i) and [Na(+)](i) rise and Na(+)-dependent plasma membrane depolarization leading to estradiol secretion.

Sertoli cell function in infertile patients with and without microdeletions of the azoospermia factors on the Y chromosome long arm.

Deletions of the azoospermia factors on the Y chromosome long arm are an important cause of male infertility, and they may involve germ cell-specific genes or ubiquitously expressed genes. To date, no clinical or hormonal parameters have yet been found to distinguish patients with and without Yq microdeletions. In particular, Sertoli cell function, as evaluated by inhibin B, has not yet been described. Our hypothesis was that microdeletions involving genes specifically expressed in germ cells should not alter Sertoli cell function. To do this, we have evaluated the testicular hormonal function in infertile patients affected by severe testiculopathies with and without Yq microdeletions, with particular emphasis on Sertoli cell function. We studied 102 well-characterized infertile patients; 27 had Yq microdeletions, and 75 were classified as idiopathic infertiles. Patients with Yq microdeletions had lower FSH and higher inhibin B plasma concentrations with respect to patients without microdeletions, suggesting that Sertoli cell function in Yq-deleted men is only partially altered. Furthermore, patients with deletions involving germ cell-specific genes had higher concentrations of inhibin B with respect to patients with deletions of ubiquitously expressed genes. These results suggested that a specific alteration of germ cells only partially influences Sertoli cell function. Hormonal status of patients without deletions suggested that in such cases the cause that has determined the spermatogenic defect may have damaged both Sertoli and germ cells. Inhibin B production in patients with Yq deletions was about 70% higher than the nondeleted patients, and the functional relationship between FSH and inhibin B was normally preserved. This study elucidated the multifactorial mechanisms underlying spermatogenic defects, where Sertoli cells may be normally functioning or damaged depending on the primary cause that has determined the testicular damage.

Evidence for FSH-dependent upregulation of SPATA2 (spermatogenesis-associated protein 2).

Here we report the cloning and characterization of a novel cDNA named spata 2. SPATA2 is the ortholog of PD1, a human testicular protein which has been suggested to play a role in spermatogenesis. The spata 2 sequence reveals an open reading frame encoding a protein of 511 amino acids. Northern blot analysis with rat mRNA demonstrated two distinct transcripts of 2.2 and 4.0 kb. Tagging recombinant SPATA2 with the green fluorescent protein (GFP) and expressing the chimeric polypeptide in HLtat transfected cells indicated that SPATA2 is located in the nucleus. RT-PCR analysis revealed that spata 2 mRNA is expressed in the testis and to a lesser extent in the brain while skeletal muscle and kidney showed a barely visible signal. The same analysis demonstrated that isolated Sertoli cells express spata 2 mRNA. Treating Sertoli cells with FSH in vitro induced remarkable changes in the steady-state level of spata 2 mRNA in a time-dependent manner. In developing testis spata 2 transcripts were first detected 10 days post partum and expression levels increased steadily with age. The ability of FSH to stimulate spata 2 mRNA expression as well as its developmental expression suggests that this protein might play a role in regulating spermatogenesis and thus, according to the Gene Nomenclature Committee, we propose the name SPATA2 (Spermatogenesis associated protein 2) for this protein (or gene).

[Analysis of sperm aneuploidy in infertile subjects after chemotherapy treatment]. / Analisi delle aneuploidie spermatiche in soggetti infertili chemiotrattati.

The continuing search for a cure for cancer has developed more aggressive therapies that may damage germ cells, leading to clinical disease in offspring of survivors. Standard therapy for the majority of cancer today consists in combinations of high doses of radiation and chemotherapy drugs. We investigated the effect of cancer treatments on the reproductive potential of men. Multicolor fluorescence in situ hybridization has been used to recognize chromosomes X, Y and 8 in sperm of 10 severely oligozoospermic subjects (sperm concentration < 5,000,000/mL) treated for cancer at least 5 years before the beginning of this study. As controls, we analyzed sperm aneuploidies in 20 fertile men (sperm concentration > 20,000,000/mL) and in 20 severe idiopathic oligozoospermic subjects (sperm concentration < 5,000,000/mL). In all subjects, X- and Y-bearing spermatozoa were present in a normal 1:1 ratio; nevertheless the frequency of 24,XY, 24,XX and 24,YY disomic sperm was significantly higher in patients treated for cancer and in idiopathic oligozoospermic subjects with respect to normozoospermic men. These results suggest that the increase in sperm aneuploidies in treated patients cannot be reported directly to precedent chemotherapy, but reflects the alteration of testicular structure, as in the case of severe idiopathic oligozoospermic subjects. With the advent of intra-cytoplasmic sperm injection, it is possible to offer the opportunity to conceive in men affected by severe oligozoospermia but it is also possible, when the spermatozoa of these subjects are used, to pass sex chromosome abnormalities on to the children. We therefore suggest caution before application of an artificial reproductive technique in severe oligozoospermic patients.

A novel gene (PD1) with a potential role on rat spermatogenesis.

PD1 is a novel protein particularly expressed at the testicular level. The relative cDNA sequences were cloned from human and rat testis libraries revealing an open reading frame for a protein of 520 and 511 amino acids respectively. The human PD1 amino acid sequence shows 85% identity with rat sequence suggesting that PD1 gene has been highly conserved during mammalian evolution. Immunohistochemical analysis showed that this protein is detected in the tubular compartment of the testis and, in particular, in the cytoplasm of the Sertoli cells. PD1 expression is not constitutive but seems to be under the influence of neighboring spermatogenic cells as demonstrated by its reduction in hypospermatogenesis with respect to normal spermatogenesis and a further reduction in Sertoli cell-only syndrome. During testicular development in the rat (from 2 to 45 days of age) the PD1 mRNA level became detectable at 14 days and then increased steadily with an advancement of age. These findings suggest that PD1 may play a role in the regulation of spermatogenesis and may be a potential candidate gene for defects of male fertility.

How can the assessment of fistula-inano be improved?

PURPOSE: Fistula-in-ano anatomy and its relationship with anal sphincters are important factors influencing the results of surgical management. Preoperative definition of fistulous track(s) and the internal opening play a primary role in minimizing iatrogenic damage to the sphincters and recurrence of the fistula. METHODS: Physical examination and endoanal ultrasound (performed with a 10 MHz endoprobe), either conventionally or with an injection of hydrogen peroxide, were performed in 26 consecutive patients. Results were matched with surgical features to establish their accuracy in preoperative fistula-in-ano assessment. RESULTS: Accuracy rates of clinical examination endoanal ultrasound, and hydrogen peroxide-enhanced ultrasound were 65.4, 50, and 76.9 percent for primary tracks, 73.1, 65.4, and 88.5 percent for secondary tracks, and 80.8, 80.8, and 92.3 percent for horseshoe extensions, respectively. Compared with physical examination and endoanal ultrasound, accuracy of hydrogen peroxide-enhanced ultrasound was higher for transsphincteric and intersphincteric primary tracks and horseshoe extensions. Both endoanal ultrasound and hydrogen peroxide-enhanced ultrasound displayed a significantly higher accuracy in detecting the internal openings (53.8 and 53.8 percent, respectively) compared with clinical evaluation (23.1 percent; P = 0.027). CONCLUSIONS: Our data suggest that hydrogen peroxide-enhanced ultrasound can be very reliable and useful in the definition of fistula anatomy, its relationship with anal sphincters, and, hence, surgical strategy. It also improves identification of secondary extensions, particularly horseshoe tracks. This method, besides being safe, economic and reputable, both preoperatively and postoperatively, could be helpful in checking operative results and recurrence.

FSH in the treatment of oligozoospermia.

The aim of this study was to individuate parameters able to distinguish oligozoospermic subjects who will respond to follicle-stimulating hormone (FSH) therapy. A group of 135 oligozoospermic subjects was divided in three groups considering basal FSH and inhibin B concentrations: group A (normal FSH and inhibin B) characterized by moderate hypospermatogenesis sometimes associated to partial spermatidic arrest; group B (high FSH and normal inhibin B) characterized by hypospermatogenesis associated or not to spermatogonial/spermatocytic arrest; group C (high FSH and low inhibin B) characterized by severe hypospermatogenesis. Seventy-eight patients were treated with FSH at the dose of 75 IU on alternate days while 57 were treated with the same dose every day for 3 months. After FSH treatment a significant increase in ejaculated sperm concentration was observed only in oligozoospermic subjects with normal basal FSH and inhibin B plasma levels (group A) showing a testicular cytological picture of moderate hypospermatogenesis. In these subjects no differences in sperm production were observed between the two protocols of therapy. In the remaining patients of group A, characterized by hypospermatogenesis associated with maturation arrest at spermatidic level and in group B and C, no increase in sperm concentration was observed after therapy. These data suggest that FSH treatment may have a role in oligozoospermic subjects only when the spermatogenetic alterations consist in germ cell depopulation without maturative disturbances and with normal FSH concentrations.

Reduced expression and altered subcellular localization of the cyclin-dependent kinase inhibitor p27(Kip1) in human colon cancer.

The p27(Kip1) protein is a negative regulator of the cell cycle and a potential tumor suppressor gene. Reduced expression of the p27(Kip1) protein has been reported in several human tumors and has been associated with higher tumor grade and increased mortality in breast, lung, colon, prostate, bladder, and gastric cancers. On the other hand, increased expression of the p27(Kip1) protein, in the absence of gene mutation, has been observed in primary colon and breast cancers. It was recently suggested that sequestration in the cytoplasm might be an alternative way to inactivate p27(Kip1)-associated inhibitory activity. This study was undertaken to further evaluate p27(Kip1) expression in primary colon tumors and to verify whether differences exist between normal and cancer tissues in terms of subcellular localization of this protein. Both normal and neoplastic tissues expressed variable amounts of the p27(Kip1) protein, as assessed by western blot analyses. Although the mean values were not different between tumor and normal mucosa samples, the expression of total p27(Kip1) was reduced in a subset of tumors. Decreased levels of total p27(Kip1) were associated with high tumor grade (P=0.03) and stage (P=0.04). Moreover, while there was no significant difference in nuclear p27(Kip1), the amount of p27(Kip1) in the cytoplasmic fraction was significantly higher in the tumor samples than in the normal mucosa samples (P=0.0001). These results suggest that p27(Kip1) expression is lost in a subset of colorectal tumors and that alterations in the subcellular localization of this protein might play a role in colon carcinogenesis.

Identification of functional binding sites for progesterone in rat Leydig cell plasma membrane.

Steroid hormones influence cell functions by binding to intracellular receptors and then acting within the nucleus. There is now evidence that steroids affect cell functions also via interaction with plasma membrane receptors in a number of different cell types. In this regard, progesterone appears to be one of the most active steroids. In this paper, we evaluate the effects of progesterone on rat Leydig cell functions, determining variations of ion homeostasis and testosterone production. This steroid was able to effect a depolarization of the plasma membrane that was due to an influx of sodium (Na+) from the external medium since it was absent when extracellular Na+ was iso-osmotically substituted with choline chloride or sucrose. The determination of intracellular sodium concentration ([Na+]i) with the Na+ -sensitive fluorescent dye sodium-benzofuran-isophtalate (SBFI) confirmed these observations. Progesterone did not modify Leydig cell intracellular calcium concentration ([Ca2+]i) at any dose tested. Furthermore, using a cell impermeant progesterone conjugate, we demonstrated that progesterone was able to stimulate Leydig cell steroidogenesis in a dose-dependent manner. The exclusion of calcium (Ca2+) from the extracellular medium did not modify the depolarizing action of progesterone and its steroidogenetic effect while in Na+ -free medium (sucrose supplemented) progesterone-stimulated effects were completely blunted. Finally, using fluorescence microscopy with a fluorescein isothiocyanate-coupled cell impermeant progesterone conjugate, we identified plasma membrane binding sites for progesterone in rat Leydig cells. These results suggest that rat Leydig cells possess progesterone receptors located on the plasma membrane, which when occupied achieves a plasma membrane depolarization, dependent on an influx of Na+ from the external medium, and the subsequent activation of steroidogenesis.

Accurate lymph-node detection in colorectal specimens resected for cancer is of prognostic significance.

PURPOSE: Lymph-node involvement is the most important prognostic factor in colorectal cancers. Many staging systems adopted node status as a parameter of tumor classification. However, the number of identified and positive glands varies across articles, depending on specimen examination. There is a consistent risk of substaging tumors and undertreating patients. Aim of this study was to investigate the prognostic significance of different pathologic methods. METHODS: Eight hundred one patients who underwent curative resection of colorectal cancer entered the study and were divided into two groups. In Group 1 the specimen was "en bloc" fixed, and nodes were identified by sight and palpation. In Group 2 the mesentery of the excised specimen was dissected away from the bowel, stretched, and pinned to cork board. The mesenteric segment surrounding the origin of principal vessels was divided from the segment surrounding the colic vessels. All specimen segments were fixed, node identification being performed by sight and palpation. Examined and positive nodes were recorded, and metastatic rate and incidence was calculated in the two groups. Patients were classified with use of different staging systems. Survival rates were calculated, related to tumor stage, and compared statistically. Pathologic procedures were included in a multivariate analysis. RESULTS: A significantly higher number of detected and positive nodes and metastatic rate (37.5 vs. 30.2 percent; P < 0.05) were observed in Group 2; 45.2 percent of Group 2 and 25.3 percent of Group 1 cases had more than three positive nodes (P < 0.05). In Group 2 several patients shifted from earlier to more advanced stages compared with Group 1 cases. Five-year and ten-year survival rates were significantly higher (P = 0.04) in Group 2 (81.5 and 77.2 percent) than in Group 1 (76.7 and 61.5 percent), mostly in patients with TNM Stage N0. Survival analysis related to Astler and Coller's and Tang's classifications confirmed such features. Higher rates of local recurrences and distant metastases were found in Group 1, particularly if related to node status (P < 0.05). Multivariate analysis demonstrated the pathologic method is an independent prognostic factor. CONCLUSIONS: This study demonstrates the prognostic impact of specimen examination. Inaccurate methods could down-stage the tumor and exclude the patient from adjuvant therapies, with detrimental effects on the outcome of the case.

Prognostic factors in colorectal cancer. Literature review for clinical application.

PURPOSE: Identification of prognostic factors is a primary basis for planning the treatment and predicting the outcome of patients with colorectal cancer. Reviewing studies from the literature performed using univariate and multivariate analyses and their own study, the authors critically discuss the prognostic value of the clinicopathologic parameters of the tumor. METHODS: Among 853 patients with colorectal tumors seen at the Department of Clinical Surgery of the Catholic University of Rome, Italy, 690 cases that were curatively resected the study. Overall survival rate, related to the clinicopathologic variables, was calculated, and univariate and multivariate analyses were performed. RESULTS: Five-year and ten-year overall survival rates were 70 and 55 percent, respectively. Univariate and multivariate analyses showed that node involvement, distant metastases, bowel obstruction, and patient gender are factors independently related to outcome. CONCLUSIONS: Data from the literature and the present study suggest that only a few clinical parameters, particularly bowel obstruction, and some pathologic factors (tumor stage, vessels invasion, and tumor ploidy) are related to patient survival rate and are the most reliable prognostic criteria. In prospective clinical studies, any other new pathologic or molecular factors should be matched with these parameters to confirm their value in outcome prediction.

Intraoperative radiation therapy in integrated treatment of rectal cancers. Results of phase II study.

PURPOSE: Risk of local recurrence of rectal cancer remains high despite extensive therapeutic strategies, many of which have been tried to achieve better local control (i.e., external beam radiation therapy (EBRT)). Recently, intraoperative radiation therapy (IORT) has been introduced in clinical protocols to boost the areas at risk of local recurrence. METHODS: Between April 1990 and December 1995, 44 patients with "high risk" (T3,N0-2 primary tumors) extraperitoneal rectal tumors and 24 patients with "locally advanced" (2 T3,N3 and 11 T4,N0-3 primary tumors; 11 local recurrences) tumors entered a protocol that included preoperative EBRT (38 Gy), surgery plus IORT (10 Gy) in the high-risk group, and preoperative EBRT (45-48 Gy) and concomitant computerized tomography (5-fluorouracil plus mitomycin C), surgery plus IORT (10-15 Gy), and postoperative adjuvant computerized tomography (5-fluorouracil plus folinic acid) in the locally advanced group. RESULTS: In the high-risk group, acute Grade 3 (Radiation Therapy Oncology Group scale) skin toxicity, attributable to preoperative treatment, involved one patient (2.2 percent); among locally advanced cases, Grade 3 hematologic toxicity was observed in one patient (4.1 percent). Treatment was discontinued in no patients. On average, IORT prolonged surgery by 48 minutes. There was no mortality. Four anastomotic leakages, one pelvic infection, and five wound infections were observed. No chronic IORT-related toxicity occurred. After mean follow-up periods of 28.3 and 25.9 months, 41 and 15 patients in the high-risk and locally advanced groups, respectively, are alive and disease-free. In one high-risk patient, an anastomotic recurrence occurred. In four patients with locally advanced tumors (1 T4 primary, 3 local recurrences) an unresectable tumor relapse developed locally. Distant metastases occurred in two high-risk patients and in eight patients with a locally advanced tumor. Three-year actuarial survival was 100 percent in both high-risk and locally advanced primary tumors and 68.2 percent in local recurrences. CONCLUSIONS: Results of this study suggest that multimodal treatment (including IORT) in rectal cancer is safe, has no significant increase of mortality and morbidity, and also shows a trend for local improvement. A longer term follow-up and larger numbers of patients could demonstrate the therapeutic efficacy of IORT in rectal cancer.

Detection of oncogene mutation from neoplastic colonic cells exfoliated in feces.

PURPOSE: Best chances of a cure from colorectal cancer are obtained before metastatic spread. Lack of specific tests allowing early diagnosis of the tumor accounts for investigation of gene alterations involved in carcinogenesis by a noninvasive method. In the present study, K-ras codons 12 and 13 mutations were studied in neoplastic cells shed from the bowel into the stool and those contained in the tumor and normal mucosa. Moreover, healthy patients and a few others with precancerous conditions were examined. METHODS: Stool, tumor, and mucosa samples were taken from 25 patients with colorectal adenocarcinoma. Stool and mucosa samples were obtained from 11 healthy patients, and stool, pathologic bowel tissue, and normal mucosa samples were obtained from 3 patients with adenoma (1) or ulcerative colitis (2). Polymerase chain reaction amplification and restriction enzyme analysis were performed. RESULTS: K-ras codon 12 mutations were detected in both tumor and stool samples of 10 cancer patients, and no gene alterations were observed in 14 patients. In one patient with a tumor, a mutation was shown in only the tumor tissue. The agreement rate in tumor and stool analysis was 96 percent. A normal pattern of K-ras codons 12 and 13 was observed in the bowel mucosa. All stool and mucosa samples from healthy patients were not altered in K-ras. Agreement was registered between samples taken from patients with preneoplastic lesions. CONCLUSIONS: These preliminary findings show a high rate of accuracy in the investigation of K-ras alterations in the colorectal cells shed into the feces, suggesting that such an approach could be used to study other gene alterations and, prospectively, to identify early colorectal cancers.

Colorectal cancer. Epidemiology, etiology, pathogenesis and prevention.

Colorectal cancer (CRC) is a neoplasm with a steadily growing incidence in Western countries. Moreover the age of 50 and over is a critical risk factor. The relationship between dietary, environmental factors and CRC has been evaluated. At present, a number of genetic risk factors such as the genetic susceptibility, tumor suppressor genes and oncogenes are thought to play a major role. The correlation of CRC with adenomatous polyps and chronic inflammatory disease, ulcerative colitis in particular, has been evaluated. Prevention of CRC is mainly based on a rational diet and in the adoption of mass screening programmes.