Ex vivo permeation of tamoxifen and its 4-OH metabolite through rat intestine from lecithin/chitosan nanoparticles.

Tamoxifen citrate is an anticancer drug slightly soluble in water. Administered orally, it shows great intra- and inter-patient variations in bioavailability. We developed a nanoformulation based on phospholipid and chitosan able to efficiently load tamoxifen and showing an enzyme triggered release. In this work the permeation of tamoxifen released from lecithin/chitosan nanoparticles across excised rat intestinal wall mounted in an Ussing chamber was investigated. Compared to tamoxifen citrate suspension, the amount of the drug permeated using the nanoformulation was increased from 1.5 to 90 times, in absence or in presence of pancreatin or lipase, respectively. It was also evidenced the formation of an active metabolite of tamoxifen, 4-hydroxy tamoxifen, however, the amount of metabolite permeated remained roughly constant in all experiments. The effect of enzymes on intestinal permeation of tamoxifen was shown only when tamoxifen-loaded nanoparticles were in intimate contact with the mucosal surface. The encapsulation of tamoxifen in lecithin/chitosan nanoparticles improved the non-metabolized drug passing through the rat intestinal tissue via paracellular transport.

Systematic review of resection of primary midgut carcinoid tumour in patients with unresectable liver metastases.

BACKGROUND: Surgery for small intestinal neuroendocrine tumours (SI-NETs) is limited by metastatic disease in most patients. However, resection of the primary lesion alone has been advocated in patients with unresectable liver metastases. The present systematic review investigated the value of surgical resection of the primary lesion in patients with unresectable metastatic disease. METHODS: MEDLINE was searched for studies reporting the outcome of patients with SI-NETs and unresectable liver metastases where there was an explicit comparison between resection of the primary lesion alone and no resection. The primary outcome was overall survival. Secondary outcomes were progression-free survival, treatment-related mortality and relief of symptoms. RESULTS: Meta-analysis was not possible, but six studies were analysed qualitatively to highlight useful information. Possible confounders in these studies were the inclusion of patients with other primary tumour sites, unknown primary tumour or non-metastatic disease. Bearing in mind these limitations, there was a clear trend towards longer survival in patients who underwent surgical resection in all studies; their median overall survival ranged from 75 to 139 months compared with 50-88 months in patients who did not have resection. The difference between the two groups was statistically significant in three studies. Data on symptomatic improvement were scarce and did not suggest a clear benefit of surgery. Surgery-related mortality seemed low. CONCLUSION: Available data suggest a possible benefit of resection of the primary lesion in patients with unresectable liver metastases, but the studies have several limitations and the results should therefore be considered with caution.

Novel platforms for oral drug delivery.

The aim of this review is to provide the reader general and inspiring prospects on recent and promising fields of innovation in oral drug delivery. Nowadays, inventive drug delivery systems vary from geometrically modified and modular matrices, more close to "classic" pharmaceutical manufacturing processes, to futuristic bio micro-electro-mechanical systems (bioMEMS), based on manufacturing techniques borrowed from electronics and other fields. In these technologies new materials and creative solutions are essential designing intelligent drug delivery systems able to release the required drug at the proper body location with the correct release rate. In particular, oral drug delivery systems of the future are expected to have a significant impact on the treatment of diseases, such as AIDS, cancer, malaria, diabetes requiring complex and multi-drug therapies, as well as on the life of patients, whose age and/or health status make necessary a multiple pharmacological approach.

Primary tumour resection in metastatic nonfunctioning pancreatic endocrine carcinomas.

BACKGROUND: The role of debulking surgery in metastatic nonfunctioning pancreatic endocrine carcinomas (M-NF-PECs) with resectable primary tumour and unresectable liver metastases is debated. AIM: Aim of the study is to evaluate whether the resection of the primary tumour in metastatic nonfunctioning pancreatic endocrine carcinoma improves survival. PATIENTS AND METHODS: Fifty-one metastatic nonfunctioning pancreatic endocrine carcinoma patients with unresectable liver metastases were enrolled from 1990 to 2004 at the time of diagnosis. Nineteen patients underwent complete resection of the primary tumour whilst 32 were judged unresectable. All cases were classified according to the WHO 2000 classification. All clinico-pathological parameters, including grade of differentiation and the Ki-67 proliferation index were considered in univariate and multivariate models. RESULTS: Of the 19 resected patients, 14 (73.7%) underwent left-pancreatectomy and 5 (26.3%) pancreaticoduodenectomy. In the unresected group of 32 patients, 9 (28.1%) underwent surgical biliary and/or gastric by-pass. There was no postoperative mortality and the median survival was 54.3 months (95% CI: 25.7-82.9). No difference in survival was observed between the two groups [resected: median 54.3 months (95% CI: 25-83.6), unresected: median 39.5 months (95% CI: 5.4-73.6); p=0.74]. Upon multivariate analysis poor differentiation (HR 3.01; 95% CI 1.08-8.4; p=0.035) and a Ki-67 index > or = 10% (HR 4.4; 95% CI 1.2-16.1; p=0.023) were significant predictors of survival. CONCLUSIONS: Resection of the primary pancreatic tumour in metastatic nonfunctioning pancreatic endocrine carcinoma patients with unresectable liver metastases does not significantly improve survival. Resection can be considered as symptomatic palliative therapy in patients with well-differentiated endocrine carcinomas and a proliferative index lower than 10%.

Prognostic factors at diagnosis and value of WHO classification in a mono-institutional series of 180 non-functioning pancreatic endocrine tumours.

BACKGROUND: Non-functioning pancreatic endocrine tumours (NF-PETs) are an aggressive gastroenteropancreatic neoplasm. The present study assessed survival, value of World Health Organisation (WHO) classification and prognostic utility of clinicopathological parameters at diagnosis. PATIENTS AND METHODS: From 1990 to 2004, 180 patients with NF-PETs were entered in a prospective database, and predictors of prognosis were tested in uni- and multivariate models. RESULTS: There were 25 (14%) benign lesions, 38 (21%) neoplasms of uncertain behaviour, 100 well-differentiated carcinomas (56%) and 17 poorly differentiated carcinomas (9%). Radical resection was possible in 93 cases (51.6%). Overall 5-, 10- and 15-year survival rates were 67%, 49.3% and 32.8%, respectively, and were significantly higher in radically resected patients (93%, 80.8% and 65.2%, respectively; P < 0.00001). By multivariate analysis, poor differentiation [hazard ratio (HR) 7.3; P = 0.0001], nodal metastases (HR 3.05; P = 0.02), liver metastases (HR 3.29; P = 0.003), K(i)-67 >5% (HR 2.5; P = 0.012) and weight loss (HR 3.06; P = 0.001) were significantly associated with mortality. CONCLUSION: This study confirms the good long-term survival of patients with NF-PETs and the prognostic value of WHO classification, liver metastases, poor differentiation, Ki-67, nodal metastases and weight loss. These latter two parameters have a prognostic value similar to that of liver metastases and Ki-67.

A case of intraductal papillary mucinous tumour following recurrent attacks of pancreatitis lasting 26 years.

We report an interesting case of a patient with neither family nor personal history for pancreatic diseases that was admitted to our department in 1982, at the age of 25 years. At that time, medical history, absence of alcohol abuse, and radiological imaging suggested a diagnosis of idiopathic chronic pancreatitis. The patient underwent a left-pancreatectomy, with histological confirmation of chronic pancreatitis. He was asymptomatic until 1988, when episodes of pain arose, requiring a pancreatico-jejunostomy. No further problems ensued until 2004 when radiological investigation following pain-related symptoms revealed enormous dilation of the pancreatic duct. A pylorus-preserving pancreaticoduodenectomy resulting in total pancreatectomy was performed. Histological examination revealed an intraductal papillary mucinous non-invasive carcinoma. Review of the previously resected specimen revealed former misdiagnosis. This tumour usually affects an elderly population and nowadays is recognised as a possible cause of chronic obstructive pancreatitis. This report represents a slippery case of misdiagnosis and demonstrates that follow-up is always mandatory following a diagnosis of idiopathic chronic pancreatitis.

Predictive factors of efficacy of the somatostatin analogue octreotide as first line therapy for advanced pancreatic endocrine carcinoma.

About 40% of nonfunctioning pancreatic endocrine carcinomas (NF-PEC) cannot be cured by surgery due to advanced stage disease. Somatostatin analogues have been proposed as first line therapy in these cases. We performed a prospective phase IV study to assess the efficacy of octreotide in advanced NF-PEC and identify factors predictive of response to therapy. Twenty-one consecutive patients with octreoscan-positive advanced-stage well-differentiated NF-PEC were treated with long-acting release octreotide 20 mg i.m. at diagnosis. The immunohistochemical expression of somatostatin receptor 2 (SSTR2) and the quantitative mRNA analysis of SSTR2 and SSTR5 were assessed in 12 tumours. The tumour proliferative fraction was assessed by immunohistochemistry for Ki-67. Eight patients (38%) had stable disease (SD) after a median follow-up of 49.5 months. Thirteen patients (62%) developed progression after a median of 18 months. Tumour progression correlated with a proliferative index>or=5% (P=0.016), weight loss (P=0.006) and absence of abdominal pain (P=0.003) at diagnosis. Other clinical (age, gender and primary tumour resection) or pathological parameters (site, size and liver metastasis) lacked significant correlation with tumour progression. No difference in the amount of SSTR2 mRNA and protein or SSTR5 mRNA was found between tumours that were stable (n=5) and seven tumours that progressed (n=7). Treatment with long-acting release octreotide was associated with stabilization of disease and a good quality of life in 38% of patients. A Ki-67 index>or=5% and/or the presence of weight loss may justify more aggressive therapy without waiting for radiologically proven progression of disease.

Development of a disease-specific Quality of Life questionnaire module for patients with gastrointestinal neuroendocrine tumours.

Quality of life (QoL) measurements are increasingly being used as an end point in cancer clinical trials. Standard generic QoL questionnaires may not assess symptoms produced by neuroendocrine tumours. Here we report the development of a disease-specific quality of life score questionnaire for patients with neuroendocrine tumours of the gut to supplement the EORTC core cancer questionnaire, the QLQ-C30. Phases 1-3 of the EORTC quality of life group guidelines for module development were used to design the new questionnaire. Forty-one relevant issues (questions) were generated after an extensive literature search. Following interviews of 15 health care workers and 35 patients, a 35 question provisional questionnaire was constructed. This was translated into seven European languages and pre-tested in 180 patients resulting in a 21-item module that will be validated in an international clinical trial. The EORTC QLQ-NET21 provides a site-specific module to supplement the QLQ-C30 for patients with neuroendocrine tumours.

[Essential thrombocythemia]. / La trombocitemia essenziale.

New diagnostic and therapeutic aspects of the essential thrombocythemia are summarized. A series of 14 patients with essential thrombocythemia is reported.

Carcinoma of pancreatic body and tail: are there improvements in diagnosis and treatment modalities over the past decade?

BACKGROUND AND AIM OF STUDY: The aim of the present study is to assess whether or not there has been improvement in the therapeutic strategy for body-tail pancreatic carcinoma over the past decade. PATIENTS AND METHODS: A total of 215 patients suffering from cytologically and histologically documented ductal carcinoma in the pancreatic body-tail, observed from 1990 to 1999, were analysed. Changes in tumour stage at diagnosis, in the percentage of patients treated surgically, in resectability rates and in the use of anticancer therapies over the years were sought. Survival curves were evaluated in relation to the treatments adopted. RESULTS: Over the 10-year period, no significant differences were observed with respect to the stage at diagnosis, resectability or type of surgery adopted. There was a significant increase in the percentage of unoperated patients (p < 0.0001) and, as expected, in the percentages of patients submitted to chemo- and/or radiotherapy (p < 0.0001). With the sole exception of tumour stage in the case of patients undergoing radiotherapy, a comparison between groups revealed no element of patient selection bias other than time. The survival of patients undergoing chemotherapy is significantly better, also at multivariate analysis, than that of patients not undergoing such therapy (13 vs. 5.8 months; p < 0.0001). CONCLUSIONS: There has been no change over the years in the direction of earlier diagnosis and the prognosis remains distinctly poor. More extensive use of anticancer therapies, however, has led to a significant increase in median survival. Radical resection, when possible, assures the longest survival.

Cystic tumours of the pancreas: a review.

The detection of a cystic tumour of the pancreas is a challenge which puts not only the surgeon's knowledge and expertise to the test, but also those of the team of radiologists and pathologists with whom he works. The diagnosis of a suspected pancreatic cystic tumour is morphological and is based on modern imaging techniques and, in the case of intraductal papillary mucinous tumours, on endoscopic findings. In the search for the correct preoperative diagnosis, however, it is of fundamental importance to bear in mind the limitations of the various instrumental investigations, and particularly those of fine-needle aspiration cytology. In this light the main morphological and clinicopathological features of serous cystadenomas, mucinous adenomas and adenocarcinomas, intraductal papillary mucinous tumours and papillary cystic and solid tumours are analysed as well as the surgical indications. In fact only the surgeon, on the basis of his knowledge of the patient's medical history and symptoms, will be in a position to determine to which nosological "cystic" entity the morphological findings described belong. A deeper knowledge of the natural history of each of these cystic tumours will help the surgeon formulate the most appropriate treatment indication. Providing the patient's condition fulfills the necessary operability criteria, resection will be mandatory whenever there exists a doubt that the tumour may be malignant or whenever its natural history suggests a malignant potential.

Infection prevention in necrotizing pancreatitis: an old challenge with new perspectives.

Necrotizing pancreatitis still remains a life-threatening disease despite several improvements in diagnosis, prevention and treatment. In recent years, some important questions have been answered such as the need for early intensive medical treatment rather than early surgery, but others are still strongly debated. The aim of this paper is to present an up-to-date assessment of current challenges in the management of necrotizing pancreatitis in order to prevent infection.

Surgical strategy in the treatment of gastrointestinal neuroendocrine tumours.

The aim of this study was to analyze the indications and type of surgery to be performed in patients suffering from the more common gastrointestinal neuroendocrine tumours. The different patterns of tumour spread are considered (local, locoregional and metastatic disease) along with the indications according to three main objectives, namely, identification of the disease, cure and care. The surgical procedures of choice in relation to the different tumour subtypes are also analyzed, and the main controversies relating to cytoreductive surgery are discussed.

Early stromal invasion in cervical cancer: immunocytochemical changes occurring in infiltrating neoplastic cells.

Early Stromal Invasion (ESI) in cervical cancer progression should be considered as a separate histological diagnostic category for its morphological characters very different from those of both carcinoma in situ (CIS) and microcarcinoma (MIC). To have some more microscopical details on these differences we performed immunocytochemical investigation addressed to evaluate, in cervical cancer malignancy progression, the evolutionary changes in the expression of some proteins involved in cell differentiation and cell cycle regulation. The results provide data improving the knowledge about ESI and supporting, with objective proofs, the nosological autonomy of ESI, with respect to CIS and MIC.

Multiple myeloma index: verification of a new prognostic approach with evaluation of treatment response.

BACKGROUND AND OBJECTIVE: Currently adopted prognostic criteria for multiple myeloma (MM) still lack reliable predictive ability to select subsets of patients for different therapies, in particular for intensive treatment protocols. In this work we aimed to test the prognostic value of the MM Prognostic Index (MMPI), developed in 1996 by Grignani et al. from Pavia University as a clinical and investigational tool. DESIGN AND METHODS: Ninety-three MM patients were eligible for the study. All received initial induction therapy based on a standard 6-month melphalan + prednisone (M + P) protocol. Clinical and laboratory parameters, conventional staging and bone marrow infiltration percentage and cytopathology (BMIC) were assessed at diagnosis, while treatment response (TR) was evaluated using criteria after induction therapy. Cox's multivariate survival analysis was applied on prognostic data. RESULTS: In our patients independent prognostic value was confirmed for British Medical Research Council staging, BMIC and TR, the three factors considered in MMPI. Risk classes obtained via MMPI identify patients with different outcomes; moreover, the index discriminates significantly among Stage II patients. INTERPRETATION AND CONCLUSIONS: This new approach to MM prognosis is simple and reliable from the prognostic point of view; it refers not only to neoplastic mass, but also to intrinsic proliferative capacity of the malignant clone and to tumor-host interactions. We recommend its adoption in clinical practice and in the evaluation and design of therapeutic trials.

Verification and comparison of two different predictive equations in Hodgkin's disease.

BACKGROUND AND OBJECTIVE: In recent years, two predictive equations to estimate median expected survival at diagnosis for patients affected with Hodgkin's disease have been developed at the University of Pavia Medical School. The present retrospective work was aimed at testing correlation between mean survival estimated using the two equations and observed survival, and at comparing the results of the two different equations. METHODS: Fifty-three deceased patients were considered from a series of 114 consecutive ones. All these patients had been treated in a conventional way according to therapeutic modalities similar to those used in the series from which the two equations were derived. Expected median survival values calculated with the older, linear equation and with the newer exponential one were compared with observed survival. RESULTS: Mean survival of the whole series was over 24 years, with survival probabilities of 85% after 5 years and 74% after 10 years. Using the first predictive equation on the 53 deceased patients resulted in a satisfactory correlation between estimated median survival and real survival: Pearson's R correlation coefficient value is 0.5996, with a t value of 5.35 and p < 0.001. The more recent exponential predictive equation showed a better correlation between estimated median survival and observed survival: R = 0.7338, t = 7.71, p < 0.001. INTERPRETATION AND CONCLUSIONS: The new exponential equation, while apparently complex, is superior to the older one, and is a very reliable and straightforward tool for estimating median expected survival: its forecast proves to be an important pretreatment parameter in every HD patient. These observations support widespread use of this tool in clinical practice to evaluate the prognosis of Hodgkin patients in a more accurate and flexible way.

Delivery of nasal powders of beta-cyclodextrin by insufflation.

PURPOSE: Delivery of nasal powders of granulated beta-cyclodextrin by insufflation was studied in order to find the relationship between powder properties and delivery behavior. METHODS: Three nasal powder formulations, prepared by granulating beta-cyclodextrin with different binders, were delivered from a powder insufflation device, in which the dose to be emitted was loaded in a gelatin capsule. The delivery sequence of powder was recorded and characterized using an image analysis program. RESULTS: Particle size was the main parameter affecting nasal powder delivery, both as to the amount of dose sprayed and the aspect of cloud produced. Between 50-150 mu m of particle size a substantial change in delivery behavior of powders was observed. Powder of around 100 mu m in size showed useful insufflation characteristics for nasal delivery. Bioavailability of nasal formulations of progesterone/beta-cyclodextrin powders was discussed in term of delivery behavior. CONCLUSIONS: The formulation approaches for improving nasal delivery of powders require the use of size optimized carriers. Insufflation of powders over 50 mu m can favour the particle deposition by impaction, whereas for powders below 50 mu m, deposition by sedimentation is moved. beta-cyclodextrin is a suitable carrier for achieving high systemic availability following nasal administration of powder formulations.