Giammario Giustozzi

Biological prognostic factors for early stage completely resected non-small cell lung cancer.

The different and unpredictable outcomes in early‐stage non–small cell lung cancer patients requires urgent research concerning the biological pathway of this neoplasm. Our study investigated the frequency of expression and the clinicopathologic and prognostic significance of a series of biological markers in stage I and II resected non–small cell lung cancer.

Locally advanced rectal cancer: a multivariate analysis of outcome risk factors.

Stages II and III rectal tumors are known as locally advanced rectal cancer (LARC) because they are characterized by a high incidence of local and distant relapses and a low probability of long‐term survival. Adjuvant treatments have been advocated to ameliorate overall survival (OS), local recurrence‐free survival (LRFS), and metastasis‐free survival (MFS) without a univocal beneficial trend. The aim of this study was to identify the independent predictive factors of OS, LRFS, and MFS which could best select patients for adjuvant treatment of LARC.

Synthesis and Secretion of Transforming Growth Factor-β1 by Human Desmoid Fibroblast Cell Line and Its Modulation by Toremifene

The present study provides evidence that the in vitro cultured fibroblast cell line from desmoid tumors differs from normal fibrobasts in its extracellular matrix (ECM) macromolecule composition and is modulated by treatment with toremifene, an antiestrogen that reduces tumor mass by an unknown mechanism. The results showed increased transforming growth factor-beta 1 (TGF-beta1) production, TGF-beta1 mRNA expression, and TGF-beta1 receptor number in desmoid fibroblasts compared with normal cells. As desmoid fibroblasts did not produce tumor necrosis factor-alpha (TNF-alpha) but were sensitive to it, which enhanced glycosaminoglycans (GAG) accumulation, we assessed the TGF-beta1 effects on TNF-alpha production by human monocytes. Our results showed TGF-beta1 significantly increased TNF-alpha secretion by monocytes. Toremifene mediated its effects in desmoid fibroblasts via an estrogen receptor-independent pathway. It inhibited GAG accumulation and the secretion of both latent and active forms of TGF-beta1 and had an inhibitory effect on TNF-alpha production by monocytes. Our results suggest that in reducing TGF-beta1 production by desmoid fibroblasts and TNF-alpha production by monocytes, toremifene may restore the balance between the two growth factors.

Effects of transforming growth factor-β1 and tumour necrosis factor-α on cultured fibroblasts from skin fibroma as modulated by toremifene

To determine how toremifene, an anti‐oestrogen triphenylethylene derivate, reduces tumour mass, we investigated its modulation of TGF‐β1 and TNF‐α in fibroma fibroblasts. Normal and fibroma fibroblasts, isolated from patients affected by Gardners syndrome without or with fibroma manifestation, were cultured in vitro. Secretion of GAG, collagen and TGF‐β1 was increased in fibroma fibroblasts compared to healthy cells. The increase in TGF‐β1 secretion into the medium was associated with a parallel increase in TGF‐β1 gene expression and receptor number. Receptor cross‐linking studies using radiolabelled TGF‐β1 revealed more receptors, particularly types I and II, in fibroma fibroblasts than in normal cells. Normal and fibroma fibroblasts did not synthesise TNF‐α, but they had TNF‐α membrane receptors, as shown by TNF‐α assay. TNF‐α secreted by human monocytes, which may be present in the peritumoral area, increased cell proliferation and GAG accumulation and was, in turn, enhanced by TGF‐β1 treatment. Both growth factors increased angiogenesis, as shown by the CAM assay. Toremifene reduced TGF‐β1 secretion by fibroma fibroblasts and TNF‐α secretion by monocytes, thus downregulating cell proliferation, ECM macromolecule accumulation and angiogenic progression. We hypothesise that increased TGF‐β1 gene expression and TGF‐β1 secretion in fibroma fibroblasts as well as the subsequent rise in TNF‐α production by monocytes may facilitate fibroma growth and that toremifene inhibits autocrine and paracrine growth factor production.

Human desmoid fibroblasts: matrix metalloproteinases, their inhibitors and modulation by Toremifene

BackgroundDesmoid tumour is a benign, non metastasising neoplasm characterised by an elevated deposition of organic macromolecules in the extracellular matrix (ECM). The matrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases involved in the degradation of ECM macromolecules. The MMPs and their natural inhibitors (TIMPs) have been implicated in tumour growth, invasion and metastasis. In this study we provide evidence that the in vitro cultured cell line from desmoid tumour accumulates more collagen fibres in the ECM than healthy fibroblasts.MethodsWe investigated collagen accumulation by 3H-thymidine incorporation, MMP expression by substrate gel zymography and TIMP expression by Western blot analysis.ResultsDesmoid fibroblasts showed a reduction in MMP activity and an increase of type I and III collagen and TIMPs compared to normal fibroblasts.ConclusionThe increase in collagen in desmoid fibroblasts was due to inhibited collagen degradation (reduction of MMP activity) rather than to increased collagen synthesis. Adding toremifene, an anti-estrogen triphenylethylene derivate, to desmoid fibroblasts reduced collagen accumulation by decreasing mRNA expression and increasing collagen degradation.

Transplantation of allogeneic/xenogeneic pancreatic islets containing coherent microcapsules in adult pigs.

WE HAVE PREVIOUSLY described a method for fabrication of alginate/polyaminoacidic CM. Thereafter, we completed assessment of either morphological properties of structural as well as ultrastructural level, or in vitro immunoselectivity, or in vivo post-transplant (Tx) functional performance in diabetic rodents of these new biomembranes for islet Tx immunoprotection in full absence of the recipient’s pharmacological immunosuppression. Because CM, unlike conventional-size microcapsules (CSM), measuring an average 600 to 800 mm in equatorial diameter, hold the unique advantage of occupying a volume which is almost coincident with that of naked islets, these new microimmunobarriers could address a number of unsolved problems with regard to encapsulated islet cell Tx in diabetic large mammalians. One of the most formidable hurdles to this approach for the therapy of insulin-dependent diabetes mellitus has consisted of inadequacy of implant sites for encapsulated islets. Because of the final excessive CSM’s Tx size, these capsules had been only implanted in the peritoneal cavity. Unfortunately, even if highly biocompatible, intraperitoneally grafted, islet-containing microcapsules had often provoked severe, possibly mass-related (60 to 80 mL/diabetic dog) inflammatory cell reaction. Dense connective tissue infiltration invariably resulted in impairment of biochemical exchange, ultimately leading to Tx failure. After testing the new CM in either in vitro functional and immunological or in vivo rodent diabetes-correction studies, we had embarked on assessment of CM biocompatibility, after multiple-site transplantation into adult pigs. Preliminarily, we have shown that empty CM, per se, indeed were biocompatible in this large-size mammal animal model, with a very low degree of sensitization being induced by repeated CM-Tx booster. In an attempt to determine whether CM, because of their minimal size, would permit access to Tx sites so far interdicted to CSM, including parenchymatous organs, with full retention of the encapsulated allogeneic/xenogeneic islet cell viability, we have transplanted porcine or canine islet containing CM into multiple Tx sites, and examined them histologically, at 30 days post-Tx, in normal, adult pigs. MATERIALS AND METHODS Animals

Acute Cellular Rejection Monitoring After Intestinal Transplant: Utility of Serologic Markers and Zoom Videoendoscopy as Support of Conventional Biopsy and Clinical Findings

Acute cellular rejection (ACR) episodes in intestinal transplant recipients are diagnosed by histologic and clinical findings. We have applied zoom video endoscopy and the use of serologic markers granzyme B (GrB) and perforin (PrF) to monitor rejection together with conventional tools. Seven hundred eighty-two blood samples (obtained at the time of the biopsy) collected from 34 recipients for GrB/PrF upregulation were positive among 64.9% of ACRs during a 3-year follow-up. Considering only the first year results posttransplantation, it reached 73.1% of rejection events. Zoom videoendoscopy was used by our group in 29 recipients of isolated intestine (n = 24) or multivisceral transplantations (n = 5) to enable observation of villi and crypt areas. From more than 270 procedures, 84% of the zoom findings agreed with the histologic results, namely, a specificity of 95%. In fact, during ongoing ACR, villi were altered in 80% of cases. Both procedures were helpful to support conventional histologic findings and clinical symptoms of ACR in intestinal transplant recipients.

Acute appendicitis in the geriatric patient

Background Acute appendicitis in geriatric patients represents the 7– 12% of all acute abdomen cases. Elderly patients with appendicitis more frequently show generalized outwearing pain, with abdominal wall rigidity and distension and appearance of abdominal mass. The difference in the clinical presentation between the young and the aged patient may be due to the elderly persons delay in addressing himself to the doctor, and not to differences in the pathologic process itself. The aim of this trial is to underline, through an analysis of the patients who underwent surgery for suspected acute appendicitis at the Division of General and Emergency Surgery of the University of Perugia, Hospital S. Maria in Terni, the clinical aspects of this pathology in the geriatric patient, in order to stress out the useful elements that may lead us to a early diagnosis and a reduced post operatory mortality.

High tie versus low tie of the inferior mesenteric artery: a protocol for a systematic review

In anterior resection of rectum, the section level of inferior mesenteric artery is still subject of controversy between the advocates of high and low tie. The low tie is the division and ligation to the branching of the left colic artery and the high tie is the division and ligation at its origin at the aorta. We intend to assess current scientific evidence in literature and to establish the differences comparing technique, anatomy and physiology. The aim of this protocol is to achieve a meta-analysis that tests safety and feasibility of the two procedures with several types of outcome measures.

Colovesical fistulae in the sigmoid diverticulitis

In most cases Colovesical fistulae are complications of diverticular disease and representing the most common kind of colodigestive fistula; less common are colovaginal, colocutaneous, coloenteric and colouterine fistula. In this article we review the literature concerning colovesical fistulae in colorectal surgery for sigmoid diverticulitis and report on two cases that required a surgical treatment, one elective and the other in emergency. In both cases we performed a sigmoid resection with a primary anastomosis and small vesical window-ectomy placing a Foley catheter for about 10 days.