Automatic procedures for the synthesis of difficult peptides using oxyma as activating reagent: A comparative study on the use of bases and on different deprotection and agitation conditions.

Solid-Phase Peptide Synthesis (SPPS) is a rapid and efficient methodology for the chemical synthesis of peptides and small proteins. However, the assembly of peptide sequences classified as "difficult" poses severe synthetic problems in SPPS for the occurrence of extensive aggregation of growing peptide chains which often leads to synthesis failure. In this framework, we have investigated the impact of different synthetic procedures on the yield and final purity of three well-known "difficult peptides" prepared using oxyma as additive for the coupling steps. In particular, we have comparatively investigated the use of piperidine and morpholine/DBU as deprotection reagents, the addition of DIPEA, collidine and N-methylmorpholine as bases to the coupling reagent. Moreover, the effect of different agitation modalities during the acylation reactions has been investigated. Data obtained represent a step forward in optimizing strategies for the synthesis of "difficult peptides".

Mean diffusivity discriminates between prostate cancer with grade group 1&2 and grade groups equal to or greater than 3.

PURPOSE: To test the potential ability of mean diffusivity (MD) and fractional anisotropy (FA) in discriminating between PCa of grade group (GG) 1&2, and GGs≥3. MATERIAL AND METHODS: Diffusion Tensor Imaging (DTI) experiments at 3T in a cohort of 38 patients with PCa (fifty lesions in total) were performed, by using different diffusion weights (b values) up to 2500s/mm(2). Gleason score (GS) and GG data were correlated with DTI parameters (MD and FA) estimated in PCa. The relation between DTI measures and GS was tested by the linear correlation analysis (Pearson's coefficient). One-way analysis of variance to check the statistical significance of the difference between GG 1&2 and GGs 3, 4, 5, ≥3 was used. Results were reported for each of the three b-values ranges: 0-800s/mm(2), 0-1500s/mm(2), 0-2500s/mm(2). RESULTS: A negative correlation was found between MD and GS. The highest linear correlation was observed when the fit was performed with data acquired in the b-values range 0-2500s/mm(2). MD values were significantly different between GG 1&2 and GG=3 and between GG 1&2 and GG ≥3. Moreover this difference is better defined when high b values (higher than b=800s/mm(2)) are used. The specificity, sensitivity and accuracy in the discrimination between GG 1&2 and GG=3 were: 90%, 66.7% and 82.4%, respectively when MD was estimated in the b-values range 0-2500s/mm(2) while these values were 85%, 58.3% and 78.4% when MD was estimated in the b-values range 0-800s/mm(2). Conversely FA did not discriminate between GG 1&2 and GG ≥3, at any investigated b-values range. CONCLUSION: This study suggests that MD estimation in PCa, obtained from DTI acquired at high b-values, can contribute to the diagnosis and grading of prostate cancer while FA is not a useful parameter for this purpose.

[Endometrial ablation versus hysterectomy in women treated with tamoxifen]. / Ablazione endometriale versus isterectomia in pazienti in trattamento con tamoxifene.

AIM: The aim of our study is the assessment of the importance of the endometrial ablation versus hysterectomy in patients treated with tamoxifen for previous breast cancer. METHODS: Fifty-eight outpatients in therapy with tamoxifen for 1 year were controlled in the Department of Gynaecology of the University of Naples. We have selected these patients in two groups: group A, with 28 women with abnormal uterine bleeding and endometrial thickness >8 mm and group B, with 30 normal endometrium asymptomatic women. All patient of group A and 18 of group B were treated with endometrial ablation. RESULTS: Next follow-up showed normal hysteroscopy figures in 89% of cases and 5% of cases needed a hysterectomy for new abnormal uterine bleeding and cytology. CONCLUSION: Our results show the utility of endometrial ablation especially in selected cases in therapy with tamoxifen for previous breast cancer.

Locoregional IL-2 therapy in the treatment of colon cancer. Cell-induced lesions of a murine model.

BACKGROUND: Local therapy with IL-2 may be very effective in the treatment of different forms of cancer. The aim of this study was to determine the effectiveness of IL-2 locoregional application in the treatment of colon cancer. MATERIALS AND METHODS: Twenty eight syngenic BDIX rats were utilized in this study. The rats were divided into two groups of fourteen animals: group T (treatment) and group C (control). All rats of both groups were injected, under the splenic capsule, with T 10(7) DHD/K2/ TRb neoplastic cells. Then, within and around the site of the previous inoculation, the T group was injected with 1 ml of glucosate solutions + 0.1% albumin (BSA) containing 2.5 x 10(6) IU of IL-2 ( Proleukin-Chiron), whereas the C group was injected with 1 ml of BSA alone. After three weeks, rats were sacrificed and the liver and spleen were removed. The following parameters were considered: volume and weight, neoplastic-non neoplastic tissue index of the spleen, mitotic index and vascular density of splenic and hepatic lesions. RESULTS: All the studied parameters showed statistically significant differences in treated and untreated animals. CONCLUSION: This study of a murine model demonstrated that IL-2 locoregional therapy may be effective in the treatment of colon cancer.

Lymphadenectomy in gastric cancer: influence on prognosis of lymph node count.

To better understand the role of the number of lymph nodes retrieved on long-term outcome of gastric cancer treatment, 154 patients who had undergone curative resection, with dissection of >15 nodes were retrospectively studied. Dissection of perigastric and extraperigastric lymph nodes, defined as 'extended' (>26 nodes dissected) in 39 cases and 'limited' (< or = 26 nodes dissected) in 115 cases, was performed. A total of 3479 lymph nodes (mean 22.6 per specimen), were dissected and of these 721 showed metastases. A mean of 8.1 lymph node metastases, per metastatic case, was found. Regression analysis showed no independent factor associated with the extent of lymphadenectomy. Depth of wall invasion (p=0.000) and histological growth pattern (p=0.044) were independently associated with the number of lymph nodes involved (pN0, pN1 1-7, pN2 >7). The cumulative 5-year survival rate was 47% in patients without lymph node metastases; 29% in those with 1-7 nodes involved and 17% in those with >8 nodes involved (p=0.002). Receiver operating characteristic (ROC) curve analysis, in 65 nodenegative cancer cases, demonstrated an area under the curve for vital status (alive or dead) of 0.602 (95% CI: 0.473 - 0.721). All node-negative cases with a number equivalent to or exceeding the cutoff point of 23 nodes were alive. ROC analysis showed 11 to be the cutoff number of metastasized lymph nodes in correlation with vital status. Almost all those patients in whom the number of positive nodes was equivalent to, or exceeded the cutoff point had died (area under the ROC curve 0.633; 95% CI: 0.524 - 0.733). ROC analysis showed that the cutoff lymph node ratio, in relation to vital status, was 0.33. The majority of patients at or above this cutoff point had died (area under ROC curve 0.682; 95% CI: 0.574 - 0.776). Multivariate survival analysis showed that lymph node ratio was the only independent prognostic factor (p=0.001). The present findings suggest that, in lymphadenectomy with at least 15 nodes, the number and status of regional nodes dissected, irrespective of the location, provide reliable prognostic information on curatively resected gastric carcinomas.

Cancer precursor lesions in intact stomach Helicobacter pylori gastritis and in resected stomach gastritis.

Hemigastrectomy for benign disease and Helicobacter pylori infection are risk conditions for the development of gastric cancer. Aim of the study was to compare gastric histology and precursor lesions of malignancy in these two conditions. The hemigastrectomy group included 351 consecutively endoscoped subjects operated for gastroduodenal benign disease. Six to ten biopsy specimens were routinely taken from the residual gastric mucosa. The intact stomach group included 2097 consecutively endoscoped symptomatic subjects, who did not receive eradication therapy against H. pylori. The histological findings were classified as normal mucosa (NM), chronic non atrophic gastritis (CNAG), chronic atrophic gastritis (CAG), intestinal metaplasia (IM) and dysplasia (DYS). One thousand and three intact stomachs were H. pylori negative, and 1094 showed H. pylori colonization. The age over fifty was a significant risk factor for the occurrence of IM (OR 2.52, P < or = 0.001) and DYS (OR 3.46, P < or = 0.001), while Hp-positivity was a risk factor for CNAG (OR 1.81, P < or = 0.001) and CAG (OR 3.88, P < or = 0.001). Gastroresection was associated to higher risk for CNAG (OR 1.53, P < or = 0.001) and DYS (OR 4.31, P < or = 0.001) and to a lower risk of CAG (OR 0.49, P < or = 0.001). Both in males and females the risk for CNAG was significantly higher in Hp-positive (males OR 1.92, P=0.000; females OR 1.70, P=0.000) and gastrectomized subjects (males OR 2.06, P=0.000; females OR 2.43, P=0.000). Gastrectomized males, furthermore, showed an increased risk for DYS (OR 5.82, P=0.000). The aged Hp-negative and Hp-positive subjects evidenced a significant risk for IM (respectively OR's 3.42, P=0.000 and 4.85, P=0.000); the risk for DYS was significant in aged Hp-negative subjects (OR 4.09 P < or = 0.020). The Hp-positive individuals evidenced a significant risk for metaplastic mucosal changes (OR 38.17, P=0.000). Subjects aged over forty at the time of surgery and those with a longer postoperative follow up endoscopy presented an increased risk for CNAG of the residual mucosa (respectively OR's 2.75, P=0.000 and 5.25, P=0.000). CNAG and IM were the most frequently observed mucosal lesions both in subjects operated for duodenal and gastric ulcer (respectively OR's 4.02, P=0.000 and 3.00, P=0.000). Our data support that hemigastrectomy for benign disease and H. pylori infection may induce an increased incidence for histological precursor lesions for gastric malignancy and suggest that carcinogenesis in a resected stomach may be different from that in the intact stomach.

Favorable toxicity profile of raltitrexed in elderly patients treated for colorectal cancer: a case series.

BACKGROUND: Age-related physiological changes may lead to an increased toxicity of chemotherapy in the elderly, thus making tumor treatment difficult in this increasing subset of patients. OBJECTIVE: Since many trials claimed a favorable therapeutic index with raltitrexed, the aim of our preliminary study was to evaluate the anticancer activity and the toxic profile of this drug in the elderly. METHODS: Thirteen elderly patients with colorectal cancer, aged 75-90 years, were enrolled in a monochemotherapy treatment with raltitrexed. Due to their advanced age, the drug was administered with a 33% reduction of the dose. RESULTS: One partial response, four disease stabilizations, and two disease progressions were observed in 7 patients with advanced colorectal cancer. The patients with response or disease stabilisation had a satisfactory time to progression. Four out of 6 patients treated in the adjuvant setting for Dukes' C colorectal cancer remain disease free at observation periods of 15+ to 29+ months. Toxicity was virtually absent in all patients. CONCLUSIONS: The activity of monochemotherapy with raltitrexed appears to be appealing, above all because it is observed in the absence of toxicity. Though recent reports suggest some concern about severe complications of treatment with raltitrexed, administration of reduced doses of this drug seems to be a putative therapy for those patients who, because of their age, are highly susceptible to the adverse effects of chemotherapy.

Maximum gastric cancer diameter as a prognostic indicator: univariate and multivariate analysis.

It was suggested that there are no stronger prognostic factors in gastric cancer than nodal involvement or depth of wall invasion. The present paper evaluated the influence of maximum tumor diameter (MTD) value, measured on fixed resected specimens, on the extent of disease progression and the outcome in gastric cancer patients. Clinicopathological data were retrospectively retrieved from records of 122 patients who underwent curative gastrectomy. The patients' MTD values were grouped as follows: MTD1, up to 26 mm; MTD2, between 26 and 50 mm; and MTD3, over 50 mm. The three groups evidenced significant differences with regard to 5 year survival (MTD1: 54%, MTD2: 31%, MTD3: 20%; p = 0.00027), furthermore they were significantly different with respect to the type of gastrectomy (p = 0.021), depth wall invasion (p = 0.000), lymphatic microinvasion (p = 0.014), perineural microinvasion (p = 0.017), stromal reaction (p = 0.025), and stage (p = 0.035). ROC curve analysis individuated a best accurate MTD threshold value for nodal involvement of 32 mm (sensitivity = 56.6%; specificity = 60.9%; positive predictive value = 52.6%; negative predictive value = 64.6%). The logistic regression analysis suggested that the depth of wall invasion was the only independent variable associated with MTD value (p = 0.0005). Multivariate analysis showed that independent prognostic risk factors were sex (p < 0.0025), number of involved nodes (p < 0.001) and MTD (p < 0.001). In conclusion, the maximum tumor diameter value of gastric cancer may be a factor with greater prognostic implications than previously believed.

Intracranial hemorrage due to brain metastases in an Italian HCV patient with hepatocellular carcinoma.

Brain metastases from hepatocarcinoma are exceptional and only a few cases have been reported in the literature, mainly from Far-Eastern countries. Clinical diagnosis in asymptomatic patients with preserved liver function is difficult and usually late. In some cases, cerebral metastasis is the initial manifestation of HCC and patients may develop intracerebral hemorrage and have a stroke-like presentation. We report on the first Italian case of cerebral metastases from multifocal hepatocellular carcinoma in an asymptomatic HbsAg negative patient with unknown HCV related chronic hepatitis and no evidence of liver cirrhosis. For many years he had a mild liver enzyme elevation and the presence of multiple misinterpreted hypoechogenic hepatic lesions. The hepatic tumor spread to the lungs and the brain and the patient developed two major episodes of intracranial hemorrage. He had two nodular lesions in the brain and alpha-fetoprotein levels were more than 10,000 ng/ml. He died from neurologic causes, without major signs of liver failure.

Presacral myelolipoma in a patient with colon carcinoma.

Myelolipoma is an uncommon benign tumor, composed of an admixture of adipose tissue and hematopoietic cells, usually discovered within the adrenal glands. Extra-adrenal myelolipomas are rare and approximately half of the reported cases were presacral. We report a case of an asymptomatic presacral myelolipoma measuring 9x8x7 cm, incidentally found in a 71-year-old woman with a stenosing colon cancer. Ultrasonography, computed tomography and magnetic resonance imaging of the presacral mass evidenced a well circumscribed tumor with heterogeneous features due to a nonuniform composition. Surgical excision of the mass was performed.

Has desmoplastic response extent protective action against tumor aggressiveness in gastric carcinoma?

A clinical assessment of protective action of desmoplastic response by limiting tumor aggressiveness has been carried out in 171 patients with gastric carcinoma, surgically treated at the First Surgical Clinic of the University of Rome "La Sapienza" between 1988-1999. A univariate statistical analysis was performed using Kaplan-Meier method for: desmoplastic reaction, age, sex, histologic type, tumor size, stage, lymphonodal status and metastases. To determine the influence of these factors on prognosis, the Cox regression was applied. We found a significant association between desmoplastic reaction extent and presence or absence of metastases (p= 0.026), lymphonodal involvement (p = 0.05), stage (p = 0.036). In the univariate analysis, survival was significantly related to sex (p = 0.012), tumor size (p = 0.009), lymphonodal involvement (p = 0.000), metastases (p = 0.000), stage (p = 0.000), desmoplastic reaction extent (p = 0.05); age and histologic type showed no relationship (p = n.s.). The desmoplastic response extent is not a protective factor against tumor invasiveness in gastric carcinoma, on the contrary it may be considered a negative prognostic factor.

Epirubicin, cisplatin and continuous-infusion 5-fluorouracil (ECF regimen) in the treatment of advanced colorectal cancer.

Thirty-one patients with advanced colorectal cancer were treated with a regimen of epirubicin, cisplatin and continuous-infusion (c.i.) 5-fluorouracil (5-FU) (ECF regimen). Twenty-seven patients were evaluable for response rate (RR), progression-free survival (PFS) and overall survival (OS). In this study, the ECF chemotherapy yielded a 51% RR with a PFS of more than 8 months, an OS of more than 11 months and tolerable toxicity. In spite of the perplexity concerning the use of anthracyclines in colorectal cancer, the ECF regimen seems to be a possible treatment even for this malignancy. Controlled studies with ECF versus standard treatments and versus 5-FU alone in c.i. are necessary.

[Benign schwannoma of the pelvic retroperitoneum. Report of a case and review of the literature]. / Lo schwannoma benigno a localizzazione pelvica retroperitoneale. Descrizione di un caso clinico e revisione della letteratura.

Benign schwannoma is a tumor arising from Schwann cells (forming the neural sheath of peripheral nerves). The retroperitoneal location is unusual (0.5-5% of cases). Most common locations are cranial nerves (especially the 8th pair) and, in peripheral nerve system the neck, mediastinum and extremities. To this date the known cases of benign retroperitoneal schwannoma are about 60, of which less than 20 in the pelvis. The low frequency of this tumor and the lack of specific instrumental signs and objective symptoms (since it develops in a deep and broad region as retroperitoneum) make presurgical diagnosis very difficult. It can be confirmed only during surgery and definitive histological examination. The information provided by ultrasonography, CT and MR help to limit diagnostic hypothesis, but they don't show any pathognomonic images. The resection of this tumor is the appropriate treatment, even though it is really a complex one. Prognosis is quite good since post-surgical recurrences are unusual. If they appear is probably because excision wasn't radical. Complete resection is the best treatment for retroperitoneal pelvic schwannoma and today it can be performed also by laparoscopy. Partial resection can be used when the mass is strongly connected to essential organs in order to prevent iatrogenic harms (neural deficit, vessel lesions); this may occur in 10% of cases. This paper describes a benign schwannoma with pelvic retroperitoneal location, incidentally discovered during a routine gynecological check up. The purpose of this study is to review current therapeutic and diagnostic techniques in retroperitoneal pelvic schwannoma (including a review of current literature) and to identify th problems that can be encountered in the differential diagnosis of this unusual disease from other neoplasms occurring in the same place.

Parietal sierosa for protecting colonic suture lines. Technical note.

Suture line leakage is a frequent, serious problem in colon surgery. We propose the use of a flap of the parietal peritoneum from the paracolic gutter, adjacent to the operative site, to protect right and left colon suture lines. The advantage of this method is that it permits complete exclusion of the sutured intestine from the peritoneal cavity and avoids the risks of leakage from an intestinal suture line within the peritoneal cavity.

[Surgery associated with intraoperative hyperthermia-chemotherapy in the treatment of malignant tumors of the digestive system with peritoneal carcinosis]. / Chirurgia associata ad ipertermochemioterapia intraoperatoria nel trattamento dei tumori maligni dell'apparato digerente con carcinosi peritoneale.

In the last two years the authors have treated 4 patients affected with malignant tumors of large bowel with very poor prognosis. In every cases they found large spreading to peritoneal cavity. These patients underwent to intraperitoneal hyperthermia-chemotherapy using a special device conceived by authors. This treatment produced promising results as related to life quality in these cases.

Isolated splenic metastasis from endometrial carcinoma.

Splenic involvement by carcinomatous metastases occurs late in the course of widely disseminated disease. Solitary metastasis to the spleen from a primary of any source is an uncommon event. We report a case of a 58-year-old woman in which an asymptomatic solitary metastatic endometrial adenocarcinoma of the spleen was detected 28 months after resection of the primary malignancy and treated by splenectomy. There are thirteen other reported cases of solitary splenic metastasis from gynecological cancers; in four of these reports the source was endometrial.

[Primary carcinoma of the cystic duct: a case report and review of the literature]. / Il carcinoma primitivo del dotto cistico: caso clinico e revisione della letteratura.

The Authors, after a short introduction concerning the primary carcinoma of the cystic duct and the exact definition according to Farrar's criteria, report a case occurred to their observation, the 35th case of international literature. In particular the importance of some hemato-clinical parameters and instrumental investigation (ERCP, angio-CT) to underlined in order to surgical indication. In the case here reported cholecystectomy uses informed with partial resection of the hepato-choledochus and excision of some periductal and pericholedochus lymph nodes. Finally, the Authors discuss about clinical data and diagnostic and therapeutic trends, on the case of their experience and literature review.

Papillary renal cell carcinoma presenting as nodal metastases to the neck.

Renal cell carcinoma, in a high percentage of patients, metastasizes early, sometimes mimicking other lesions. We present a case of an asymptomatic papillary renal cell carcinoma that presented neck metastases as the initial manifestation. The laterocervical and supraclavicular masses were considered consistent with nodal metastases from a thyroid nodule. A hemithyroidectomy was performed before the renal tumor was diagnosed. Then the patient underwent a left-side radical nefrectomy. We discuss the unpredictability of the clinical course of renal cell carcinoma.