Gemcitabine plus irinotecan as first-line weekly therapy in locally advanced and/or metastatic pancreatic cancer.

Single-agent gemcitabine has been established as standard treatment for advanced pancreatic cancer since clinical studies have shown an improvement in overall survival and significant clinical benefit when compared to the best supportive care despite low overall objective response. Several phase II studies have tested other single agents and different gemcitabine-based regimens in pancreatic cancer, but both response and survival rates have remained low. Irinotecan, a topoisomerase I inhibitor currently approved for the treatment of metastatic colon cancer, has also demonstrated improved response rate in patients with pancreatic cancer. Our purpose was to determine the activity and toxicity of this regimen in patients with unresectable or metastatic pancreatic cancer. Patients with histologically confirmed pancreatic adenocarcinoma received gemcitabine 1000 mg/m2 plus irinotecan 100 mg/m2 IV on days 1, 8, and 15 of a 28-day cycle for 6-8 months. From February 2004 to April 2006, 33 patients were entered into this study, 32 of whom were evaluable for treatment response, toxicity, median time to progression, and median survival. Characteristics included a median age of 63 years (range 41-79), 21 males (64%), and 12 females (36%). One patient discontinued treatment due to adverse effects. The total number of cycles administered was 188 and the median number of cycles for patients was 5.6 (range 2-7). Thirty-two patients were assessable for toxicity and response. Grade 3 hematological toxicity occurred in 9% of patients and was primarily neutropenia. No grade >2 gastrointestinal toxicities or death due to treatment were observed. The most frequent nonhematological adverse event was fatigue. Ten patients responded to treatment with two complete responses (6.3%) and eight partial responses (25.0%), for an overall response rate of 31.3%; 11 patients achieved stable disease (34.3%). The median time to tumor progression and the median survival were 9.2 (95% CI: 6.0-12.4) and 11.8 (95% CI: 7.7-15.9) months, respectively, with a 2-year survival of 22%. On the basis of this trial, the combination of gemcitabine plus irinotecan, administered in a weekly schedule and at this dose, is well tolerated and offers encouraging activity in the treatment of advanced and/or metastatic pancreatic cancer.

Immediate transmucosal implant placement in molar extraction sites: a 12-month prospective multicenter cohort study.

AIM: To assess the clinical and radiographic outcomes of immediate transmucosal placement of implants into molar extraction sockets. STUDY DESIGN: Twelve-month multicenter prospective cohort study. MATERIAL AND METHODS: Following molar extraction, tapered implants with an endosseous diameter of 4.8 mm and a shoulder diameter of 6.5 mm were immediately placed into the sockets. Molars with evidence of acute periapical pathology were excluded. After implant placement and achievement of primary stability, flaps were repositioned and sutured allowing a non-submerged, transmucosal healing. Peri-implant marginal defects were treated according to the principles of guided bone regeneration (GBR) by means of deproteinized bovine bone mineral particles in conjunction with a bioresrobable collagen membrane. Standardized radiographs were obtained at baseline and 12 months thereafter. Changes in depth and width of the distance from the implant shoulder (IS) and from the alveolar crest (AC) to the bottom of the defect (BD) were assessed. RESULTS: Eighty-two patients (42 males and 40 females) were enrolled and followed for 12 months. They contributed with 82 tapered implants. Extraction sites displayed sufficient residual bone volume to allow primary stability of all implants. Sixty-four percent of the implants were placed in the areas of 36 and 46. GBR was used in conjunction with the placement of all implants. No post-surgical complications were observed. All implants healed uneventfully yielding a survival rate of 100% and healthy soft tissue conditions after 12 months. Radiographically, statistically significant changes (P<0.0001) in mesial and distal crestal bone levels were observed from baseline to the 12-month follow-up. CONCLUSIONS: The findings of this 12-month prospective cohort study showed that immediate transmucosal implant placement represented a predictable treatment option for the replacement of mandibular and maxillary molars lost due to reasons other than periodontitis including vertical root fractures, endodontic failures and caries.

Effect of chlorhexidine digluconate on different cell types: a molecular and ultrastructural investigation.

Although several studies have shown that chlorhexidine digluconate (CHX) has bactericidal activity against periodontal pathogens and exerts toxic effects on periodontal tissues, few have been directed to evaluate the mechanisms underlying its adverse effects on these tissues. Therefore, the aim of the present study was to investigate the in vitro cytotoxicity of CHX on cells that could represent common targets for its action in the surgical procedures for the treatment of periodontitis and peri-implantitis and to elucidate its mechanisms of action. Osteoblastic, endothelial and fibroblastic cell lines were exposed to various concentrations of CHX for different times and assayed for cell viability and cell death. Also analysis of mitochondrial membrane potential, intracellular Ca2+ mobilization and reactive oxygen species (ROS) generation were done in parallel, to correlate CHX-induced cell damage with alterations in key parameters of cell homeostasis. CHX affected cell viability in a dose and time-dependent manners, particularly in osteoblasts. Its toxic effect consisted in the induction of apoptotic and autophagic/necrotic cell deaths and involved disturbance of mitochondrial function, intracellular Ca2+ increase and oxidative stress. These data suggest that CHX is highly cytotoxic in vitro and invite to a more cautioned use of the antiseptic in the oral surgical procedures.

Lymphangiogenesis in Crohn's disease: an immunohistochemical study using monoclonal antibody D2-40.

Crohn's disease (CD) is a chronic inflammatory bowel disorder of unknown etiology. An involvement of the intestinal lymphatic system has been suggested. Recently, monoclonal antibodies have become available to distinguish lymphatic vessels from blood vessels. The aim of the study was to examine the distribution of lymphatic vessels in ileal and colic walls of patients affected by CD and compare it with healthy controls and other inflammatory bowel diseases. Twenty-eight cases of CD, 13 cases of other inflammatory bowel diseases, and 10 normal ileal and colic walls were studied. Immunohistochemical staining was performed using the monoclonal antibody D2-40. Quantification of lymphatic vessels was performed by identifying four fields with high density of lymphatics and then counting the number of lymphatic vessels at high resolution. Lymphatic diameter was also evaluated by using an ocular micrometer. Lymphatic vessels showed the highest density in CD specimens. The median number of lymphatics was significantly higher both in ileal and colic samples of CD than the other inflammatory diseases as well as normal controls. Moreover, in patients with CD, diffuse lymphangiectasia was also observed. The present data suggest that lymphangiogenesis and lymphangiectasia probably play a role in the pathogenesis of CD.

Oxaliplatin, 5-fluorouracil/leucovorin and epirubicin as first-line treatment in advanced gastric carcinoma: a phase II study.

The association between oxaliplatin and 5-fluorouracil (5-FU) has been extensively reported to improve prognosis of gastric cancer patients. The present study is aimed at evaluating response rate and the toxicity profile of the association with oxaliplatin, 5-FU/lecovorin and epirubicin in gastric cancer patients with locally advanced or metastatic disease. Thirty-six patients have been enrolled and 35 evaluated. The treatment schedule was oxaliplatin (100 mg m(-2)), 5-FU (400 mg m(-2)), leucovorin (40 mg m(-2)) and epirubicin (60 mg m(-2)) intravenously. administered every 3 weeks for 6 months, for a total of 185 therapy cycles . Response rate and toxicity were assessed according to the international WHO criteria. Every patient received a mean of 5.3 therapy cycles in a day-hospital setting. Sixteen of 35 patients (46%) showed an objective response, two complete response and 14 partial response. Median time to progression was 33 weeks with an overall median survival of 49 weeks. During the study, anaemia grade 3 and neutropenia grade 3 were observed in 9 and 11% of patients respectively. A grade 3 periferic sensorial neuropathy was observed in 6% of patients. No life threatening or cardiac toxicity was recorded. The regimen used showed anticancer activity against gastric carcinoma, a tolerable toxicity profile and excellent patient compliance.

Selection of patients for myocardial perfusion scintigraphy based on fuzzy sets theory applied to clinical-epidemiological data and treadmill test results.

Coronary artery disease (CAD) is a worldwide leading cause of death. The standard method for evaluating critical partial occlusions is coronary arteriography, a catheterization technique which is invasive, time consuming, and costly. There are noninvasive approaches for the early detection of CAD. The basis for the noninvasive diagnosis of CAD has been laid in a sequential analysis of the risk factors, and the results of the treadmill test and myocardial perfusion scintigraphy (MPS). Many investigators have demonstrated that the diagnostic applications of MPS are appropriate for patients who have an intermediate likelihood of disease. Although this information is useful, it is only partially utilized in clinical practice due to the difficulty to properly classify the patients. Since the seminal work of Lotfi Zadeh, fuzzy logic has been applied in numerous areas. In the present study, we proposed and tested a model to select patients for MPS based on fuzzy sets theory. A group of 1053 patients was used to develop the model and another group of 1045 patients was used to test it. Receiver operating characteristic curves were used to compare the performance of the fuzzy model against expert physician opinions, and showed that the performance of the fuzzy model was equal or superior to that of the physicians. Therefore, we conclude that the fuzzy model could be a useful tool to assist the general practitioner in the selection of patients for MPS.

Selection of patients for myocardial perfusion scintigraphy based on fuzzy sets theory applied to clinical-epidemiological data and treadmill test results

Coronary artery disease (CAD) is a worldwide leading cause of death. The standard method for evaluating critical partial occlusions is coronary arteriography, a catheterization technique which is invasive, time consuming, and costly. There are noninvasive approaches for the early detection of CAD. The basis for the noninvasive diagnosis of CAD has been laid in a sequential analysis of the risk factors, and the results of the treadmill test and myocardial perfusion scintigraphy (MPS). Many investigators have demonstrated that the diagnostic applications of MPS are appropriate for patients who have an intermediate likelihood of disease. Although this information is useful, it is only partially utilized in clinical practice due to the difficulty to properly classify the patients. Since the seminal work of Lotfi Zadeh, fuzzy logic has been applied in numerous areas. In the present study, we proposed and tested a model to select patients for MPS based on fuzzy sets theory. A group of 1053 patients was used to develop the model and another group of 1045 patients was used to test it. Receiver operating characteristic curves were used to compare the performance of the fuzzy model against expert physician opinions, and showed that the performance of the fuzzy model was equal or superior to that of the physicians. Therefore, we conclude that the fuzzy model could be a useful tool to assist the general practitioner in the selection of patients for MPS.

Osteonecrosis of the jaws in periodontal patients with a history of bisphosphonates treatment.

BACKGROUND/AIM: Osteonecrosis of the jaws is being increasingly reported in patients with bone metastasis from a variety of solid tumours and disseminated multiple myeloma receiving intra-venous bisphosphonates. The signs and symptoms that may occur before the appearance of clinical evident osteonecrosis include changes in the health of periodontal tissues, non-healing mucosal ulcers, loose teeth and unexplained soft-tissue infection. A series of nine periodontally involving patients showing osteonecrosis of the jaws that appeared following the intra-venous use of bisphosphonates is reported. MATERIAL AND METHODS: Nine consecutive patients with osteonecrosis of the jaws were prospectically studied. Patients' past medical histories and the drugs that they had received for their malignant disease were systematically documented. Clinical, histopathological and radiographic features and proposal for treatment modalities of osteonecrosis are also reported. RESULTS: Of the nine patients (six women and three men) observed, all had osteonecrosis in the mandible; two had maxillary involvement as well. All nine patients had a history of extraction of periodontally hopeless teeth preceding the onset of osteonecrosis. In two patients, the lesions also appeared in edentulous areas spontaneously. All the patients had received intra-venous bisphosphonates as treatment for their disseminated haematological neoplasms or metastatic bone disease. The duration of bisphosphonate therapy at presentation ranged from 10 to 70 months (median: 33 months). CONCLUSIONS: Jaw osteonecrosis appears to be associated with the intra-venous use of bisphosphonates. Dental professionals should be aware of this potentially serious complication in periodontal patients receiving long-term treatment with bisphosphonates.

Counting of platelet derived growth factor and transforming growth factor-beta in platelet-rich-plasma used in jaw bone regeneration.

AIM: Growth factors (GFs) as platelet derived growth factor (PDGF) and transforming growth factor (TGF-beta), found in platelet beta-granules also present in platelet-rich-plasma (PRP), accelerate bone revascularization and regeneration and for this reason they have been employed successfully in dental and maxillofacial surgery. Platelet concentrate is commonly used for this purpose as long as platelet release reaction and the consequent GFs loss are avoided. To reduce this phenomenon we set up an easy and fast procedure for preparing a satisfying clotted PRP by adding CaCl2 only (no exogenous thrombin). METHODS: ELISA essay has been used to measure PDGF and TGF-beta in plasma, platelets and serum and platelet GMP-140, with the cytofluorometric technique in order to quantify the degranulation entity. RESULTS: In the 13 examined patients receiving clotted PRP to enhance bone regeneration in post-extractive alveolar sockets, PRP showed no sign of platelet activation (degranulation) and short recalcification times (8-12 min). The autologous clotted PRPs specimen have been evaluated in laboratory in terms of GFs percent: 76% of initial GFs content could be recovered in clotted PRP. This result confirms the absence of platelet degranulation in our procedure. CONCLUSIONS: Significant clinical results in alveolar bone regeneration are reached only with a high percentage of GFs inserted in bone matrix, avoiding early platelet degranulation.

Clinical signs of pneumonia in children: association with and prediction of diagnosis by fuzzy sets theory

The present study compares the performance of stochastic and fuzzy models for the analysis of the relationship between clinical signs and diagnosis. Data obtained for 153 children concerning diagnosis (pneumonia, other non-pneumonia diseases, absence of disease) and seven clinical signs were divided into two samples, one for analysis and other for validation. The former was used to derive relations by multi-discriminant analysis (MDA) and by fuzzy max-min compositions (fuzzy), and the latter was used to assess the predictions drawn from each type of relation. MDA and fuzzy were closely similar in terms of prediction, with correct allocation of 75.7 to 78.3 percent of patients in the validation sample, and displaying only a single instance of disagreement: a patient with low level of toxemia was mistaken as not diseased by MDA and correctly taken as somehow ill by fuzzy. Concerning relations, each method provided different information, each revealing different aspects of the relations between clinical signs and diagnoses. Both methods agreed on pointing X-ray, dyspnea, and auscultation as better related with pneumonia, but only fuzzy was able to detect relations of heart rate, body temperature, toxemia and respiratory rate with pneumonia. Moreover, only fuzzy was able to detect a relationship between heart rate and absence of disease, which allowed the detection of six malnourished children whose diagnoses as healthy are, indeed, disputable. The conclusion is that even though fuzzy sets theory might not improve prediction, it certainly does enhance clinical knowledge since it detects relationships not visible to stochastic models.

Clinical signs of pneumonia in children: association with and prediction of diagnosis by fuzzy sets theory.

The present study compares the performance of stochastic and fuzzy models for the analysis of the relationship between clinical signs and diagnosis. Data obtained for 153 children concerning diagnosis (pneumonia, other non-pneumonia diseases, absence of disease) and seven clinical signs were divided into two samples, one for analysis and other for validation. The former was used to derive relations by multi-discriminant analysis (MDA) and by fuzzy max-min compositions (fuzzy), and the latter was used to assess the predictions drawn from each type of relation. MDA and fuzzy were closely similar in terms of prediction, with correct allocation of 75.7 to 78.3% of patients in the validation sample, and displaying only a single instance of disagreement: a patient with low level of toxemia was mistaken as not diseased by MDA and correctly taken as somehow ill by fuzzy. Concerning relations, each method provided different information, each revealing different aspects of the relations between clinical signs and diagnoses. Both methods agreed on pointing X-ray, dyspnea, and auscultation as better related with pneumonia, but only fuzzy was able to detect relations of heart rate, body temperature, toxemia and respiratory rate with pneumonia. Moreover, only fuzzy was able to detect a relationship between heart rate and absence of disease, which allowed the detection of six malnourished children whose diagnoses as healthy are, indeed, disputable. The conclusion is that even though fuzzy sets theory might not improve prediction, it certainly does enhance clinical knowledge since it detects relationships not visible to stochastic models.

The influence of new technologies on laparoscopic adrenalectomy: our personal experience with 91 patients.

BACKGROUND: Laparoscopic adrenalectomy has proved to be the technique of choice for managing benign pathologies of the adrenals and isolated adrenal metastases, especially those arising from lung tumor, but the procedure should not be performed for primitive adrenal carcinoma. The Authors wanted to test the advantages of the Harmonic Scalpel in laparoscopic adrenalectomy. METHODS: From April 1995 to April 2001, the authors investigated their series of laparoscopic adrenalectomies performed at the Careggi General Hospital, Division of General and Vascular Surgery, Florence, Italy. This study enrolled 91 patients with various adrenal pathologies. The transperitoneal approach was used, with the patient in a lateral position, as suggested by Gagner. Special care was taken to improve the surgical approach to the adrenals by the use of new technological devices such as the Harmonic Scalpel. The operative time required by the surgical procedure was computed by dividing the study into three periods: 1995-1997, 1998-1999, 2000-2001. The first period was necessary to complete the learning curve. In the second period, a steady state in surgical time was reached. During the third period, the Harmonic Scalpel was introduced. The differences between the three periods were tested using a nonparametric analysis (Mann-Whitney U test or Kruskal-Wallis test) as appropriate. A two-tailed p value of 0.05 or less was considered statistically significant. The authors investigated the cost of the operation performed in each of the two groups using, respectively, the conventional laparoscopic device (1998-1999) and the Harmonic Scalpel (2000-2001). The following expenses were considered: Harmonic Scalpel impulse generator and disposable shears, operating room cost per hour, and endoclip applier. RESULTS: The 91 laparoscopic adrenalectomies were performed with these indications: 31 incidentalomas (26 adenomas and 5 cysts), 25 cases of Conn's disease, 18 cases of Cushing's disease, 9 pheochromocytomas, 2 myelolipomas, 5 metastases (from lung, kidney, and breast) and 1 primitive carcinoma diagnosed preoperatively. Considering the whole series (1995-2001), there was a significant trend of reduction in operative time (p = 0.0001). Moreover looking at the first period (1995-1997), in which the learning curve was completed, the mean surgical time was 148 min, as compared with 125 mm. For the second period (1998-1999) (p = 0.0002). This represents a significant reduction in operative time. The authors noted a further reduction in the operative time when surgery was performed with the Harmonic Scalpel (2000-2001) (92 min; p = 0.001). The reduction in operative time attributable to the Harmonic Scalpel was confirmed also by a multivariate analysis of covariance general linear models procedure (GLM), which accounts for several confounders: age, gender, site and size of tumors, and histology (p = 0.0001). The rate was 3.3% for morbidity, 1.1% for mortality, and 2.2% for conversion. There was no difference in complications between patients treated with conventional devices and those treated with the Harmonic Scalpel. CONCLUSIONS: The laparoscopic approach has proved to be an extremely reliable procedure for benign pathologies and isolated metastases. There may yet be doubts about its use for the treatment of adrenal carcinomas preoperatively diagnosed. When surgery is performed using Harmonic Scalpel, operative time is significantly reduced and surgery is easier and less expensive. Infact use of the Harmonic Scalpel allowed the cost per operation to be reduced $70. Moreover, if surgery is performed using the nondisposable clip applier, the expenses are reduced $105.

[Laparoscopic approach to the "acute" and "chronic" bowel obstruction]. / Approccio laparoscopico alle occlusioni "acute" e "croniche" del piccolo intestino.

AIM OF THE STUDY: To retrospectively evaluate a series of patients with acute and chronic small bowel obstruction and discuss the indications of laparoscopic vs laparotomic approach and the outcome of both these techniques. PATIENTS AND METHOD: 85 patients with acute and chronic small bowel obstruction who underwent to either emergency or elective surgery since January 1999 up to October 2001 were enrolled. Subjects were divided into three groups: 39 treated with emergency laparotomy (group I), 13 with emergency laparoscopy (group II) and 33 with elective laparoscopy for chronic/subacute obstructions (group III). RESULTS: 1) the most frequent indication of the laparotomic approach was either multiple or major previous surgery as well as neoplastic diseases; 2) patients of the second group had frequently previous either minor or laparoscopic surgery; 3) the incidence of previous emergency surgery were maximum among the III group; 4) both post-operative ileus and mean hospital stay lasted less in the II than in the I group. The mean operative time and the morbidity was equal in the two groups; 5) we observed more intra-operative complications, a higher conversion rate and a longer both post-operative ileus and mean hospital stay in the II than in the III group. CONCLUSIONS: Our data support the role of laparoscopy in patients with chronic/subacute small bowel obstruction. Patients with acute obstruction may undergo laparoscopy after a careful selection, excluding subjects with previous either multiple or major surgery as well as neoplastic diseases. Such results need future confirmations from prospective randomized studies.

[Odontogenic chronic maxillary sinusitis: regenerative possibilities of oro-antral defect]. / La sinusite cronica mascellare di origine odontogena: possibilità rigenerative del difetto osseo antrale.

Odontogenic maxillary sinusitis often develops into a chronic picture of unilateral inflammation, progressively interesting the whole antrum mucosa. The only decisive therapy of this pathology is a surgical one that, by completely removing pathologic tissues, starts sinus restoration by a healthy respiratory mucous membrane. This tissue grows from the nasal cavity after the radical surgery (according to Caldwell-Luc), presupposing an antrum drainage through that same cavity. Nevertheless, if the inflamed area is just limited in the central and posterior recesses, and the hiatus semilunaris of the medial wall remains open, it is possible to avoid a surgical access to the nasal cavity. In this way, an alternative surgery is proposed for chronic sinusitis which, using principles of Guided Bone Regeneration, permits to completely remove pathologic tissues and to start bone reformation in the damaged alveolar.

Management of upper respiratory tract infections in primary care in Italy: a national survey.

This prospective study, carried out in Italy during the winter of 1998 by the means of questionnaires, was designed to investigate the diagnostic and therapeutic approach of the Italian general practitioners (GPs) to the management of acute upper respiratory tract infections (URTIs) in adult outpatients. A total of 354 GPs were questioned about ten adult patients each who had visited the surgery with an URTI requiring an antibiotic prescription. Our data showed there was a tendency to prescribe antibiotics only on the basis of clinical diagnosis, microbiological investigations being required very rarely. Orally administered antibiotics were preferred and compliance with the number of daily doses strongly influenced the antibiotic prescription. In patients affected by more severe infections, injectable antibiotics were frequently prescribed.

Short course therapy with cefitbuten versus azithromycin in pediatric streptococcal pharyngitis.

OBJECTIVE: To compare the safety and efficacy of a short course (5 days) of ceftibuten vs. azithromycin for 3 days for treatment of group A beta-hemolytic streptococcal (GABHS) pharyngitis in children. METHODS: A multicenter, open label, prospective, randomized trial in which patients > or =3 to < or =16 years of age with proven GABHS pharyngitis were randomized to receive either once daily ceftibuten for 5 days or azithromycin for 3 days. Patients were evaluated for clinical outcomes and/or for adverse events at days 6 to 8, 13 to 15 and 33 to 35 posttherapy. Microbiologic assessments (pharyngeal cultures) were conducted at baseline and at each follow-up visit. RESULTS: A total of 132 patients in the ceftibuten arm and 116 in the azithromycin arm were enrolled in the safety analysis, whereas 126 and 101, respectively, were enrolled for ceftibuten and azithromycin efficacy evaluation. Clinical success (cure or marked amelioration) at days 6 to 8 was recorded in 98 and 94% in the 2 groups, respectively. In the bacteriologic efficacy analysis at 6 to 8 days, the GABHS strain was eradicated in 76% of the patients treated with ceftibuten and in 76% of those receiving azithromycin. At 33 to 35 days, 84% of the patients in the ceftibuten arm and 71% in the azithromycin arm were GABHS-negative, and bacteriologic relapse was observed in 4 and 7% of the ceftibuten and azithromycin cases, respectively. Both treatments were well-tolerated by all patients. CONCLUSIONS: Ceftibuten and azithromycin allow simple treatment schedules (i.e. once daily administration, short duration of treatment). The somewhat higher eradication rate recorded after ceftibuten administration is consistent with the overall superior bactericidal activity of beta-lactams compared with macrolides vs. GABHS in vitro.

[New development in Crohn's disease: ++unravelling the mystery and its reinstatement as a surgically treatable condition. Part 2. Potential etiopathogenesis of "terminal ileitis" and extension of the disease to mesenteric small intestine and the colon]. / Novità per la malattia di Crohn: la soluzione dei suoi misteri dottrinali ed il suo recupero come malattia di competenza chirurgica. Nota 2. L'eziopatogenesi probabile della "ileite terminale" e l'espansione della malattia nel tenue mesenteriale e nel colon.

INTRODUCTION: The aetiopathogenesis of terminal ileitis is still unknown, as is the cause of its spread to the small and large bowel. The aim of this study was to shed light on these unknown aspects of Crohn's disease. CONCLUSIONS: The lack of patency of the ileal branch of the ileocolic lymphatic collector which causes terminal ileitis, usually in the earlier part of life, is likely to occur in the foetus around the 10th week of pregnancy as a result of a minor abnormality of the physiological regression of the vitelline duct. Excessive atrophy of the lymphatic network seems to occur, also affecting the rudimentary lymphatic vessels in the midgut destined to become the terminal ileum. The terminal ileitis spreads to the large bowel in an increasing percentage of cases and is directly related to duration of the disease, causing first ileitis plus right colitis, and then ileitis plus total colitis (which, however, does not include the rectum). It may also include the jejunum, causing skip lesions. This spread of lesions is not due to any genetic predisposition (that is to say, it is not predetermined in empirical terms), but rather to the extent of the lymphatic obstruction caused by the spread of immunocomplexes via the lymphatic network. This is shown by the fact that secondary lesions of the jejunum and large bowel are also typical of lymphoedema and that their spread is segmentary. In the light of these pathogenetic mechanisms, it is reasonable to assume that the spread of the process from the ileum to the colon might be prevented by prompt surgery during the initial phase of the ileitis. If these views are correct, the traditional subdivision of Crohn's disease forms into ileitis, ileocolitis and solitary colitis should be replaced by a very simple scheme showing the spread of the primary ileitis very often to ileocolitis, first confined to the right colon and then total. We cannot include either solitary colitis (not clearly defined in the literature) or anorectal Crohn's disease (whose forms have yet to be fully acknowledged) in this scheme.

[New developments in Crohn's disease: solution of doctrinal mysteries and reinstatement as a surgically treatable disease. 1. The process is not a form of enteritis but lymphedema contaminated by intestinal contents]. / Novità per la malattia di Crohn: la soluzione dei suoi misteri dottrinali ed il suo recupero come malattia di competenza chirurgica. Nota 1. Il processo crohniano non è quello di un'enterite, ma di un linfedema inquinato dal contenuto intestinale.

INTRODUCTION: It is unanimously acknowledged that the aetiopathogenesis of Crohn's disease (CD) is still a mystery despite the fact that almost 70 years have elapsed since it nosological identification. Another mystery and major problem of CD of the bowel is its histopathology, which has yet to be clarified; consequently, we do not know what kind of disease it is, that is to say, which process, among the ones known to us, it actually corresponds to. MATERIAL AND METHODS: The present paper presents the results of a new histopathological interpretation of the disease on the basis of 100 surgical cases of Crohn's ileitis and ileocolitis. RESULTS AND CONCLUSIONS: The disease is not a form of enteritis, but a lymphoedema of the intestinal wall, caused by a congenital lack of patency of the mesenteric lymphatic collectors, giving rise to stasis of lymph in the lymphatic network of the corresponding bowel segment and consequently to hypertension which dilates the lymph vessels in the intestinal wall. The lymph, which cannot be reabsorbed by the veins, because the venous wall denies entry to protein macromolecules, accumulates in the interstitial space with the result that the intestinal wall thickens considerably. Since the process takes place in the intestine perfused by a continuous flow of septic matter, the process is complicated by the development of lymphocytic lymphangitis, which occurs throughout almost the entire lymphatic network, obstructing the dilated lumen, limiting the dispersion of lymph and preventing gross spread of the intestinal contents into the dilated lymphatic vessels. The lymphocytic lymphangitis causes "transparietal phlogosis", which is rightly regarded as a characteristic of the disease, but is wrongly interpreted by those who have studied it. This transparietal phlogosis is neither excessive nor disproportionate to its task of obstructing the intestinal contents; it is transparietal because the lymphatic network where it takes places is itself transparietal. The reactive lymphocytic lymphangitis prevents the gross spread of the intestinal contents into the dilated lymphatic network, as stated above, but cannot prevent the limited uptake of dissolvable toxic bacterial substances (FMLP, PG-PS, LPS) conjugated in immuno-complexes. The immuno-complexes developing in the lymphatic network undergo lymph- and blood-borne spread, causing; obstructive lymphangitis in branches of the mesenteric lymphatic collectors which are still patent, increasing the degree of lymphatic obstruction and thus the extent of the intestinal lesions; general complications of so-called "metastatic Crohn's disease", which were once interpreted as autoimmune processes, but actually correspond to forms of vasculitis which may be localised in any of the organs or apparatuses of the body, sometimes proving extremely serious. Lymph dispersion in the intestinal lumen, causes not only diarrhoea, but often also lymphocytopenia and hypoproteinaemia, and therefore an immunodepression syndrome, which in the long term may give rise to intestinal and extraintestinal cancer.

[New developments in Crohn's disease: unravelling the mystery of its etiopathogenesis and its reinstatement as a surgically treatable condition. Part 3: The rational principles of surgical therapy]. / Novità per la malattia di Crohn: la soluzione dei suoi misteri dottrinali ed il suo recupero come malattia di competenza chirurgica. Nota 3. I principi razionali della terapia chirurgica.

The diagnosis of Crohn's disease makes surgery mandatory in any form of the disease, because it is ingravescent, spreads in the bowel, and is unresponsive to any type of pharmacological treatment; it invariably involves major consequences and often leads to serious complications such as perforation and cancer in the long term. The operation has to be performed promptly, because the commonest complications, such as obstruction and perforation, may occur at any stage of the disease, including the initial phase. Moreover, it is advisable to prevent the spread of the disease to the colon and jejunum, which occurs in increasing percentages of patients and is related to duration of the disease. As a rule, surgery has to take the form of a resection of the diseased bowel, which includes not only the lesions already in progress, but also those which may be expected to develop. Therefore, since the disease is segmentary, the resection, too, has to be segmentary, even when part of the diseased segment is apparently sound. Inadequate resection is often followed by dehiscence of the anastomosis and sooner or later by an inevitable recurrence. Three types of resection are performed for Crohn's disease depending on whether it manifests as ileitis, ileitis plus right colitis, or ileitis plus right and left colitis. Ileitis requires an ileocolic resection. Because the resection has to be segmentary and the proximal limit of the segment, i.e. of the lesions, cannot be determined at external examination of the intestine, the surgeon has to perform an approximate, temporary resection and examine the resected specimen, open along its entire length, before constructing the anastomosis. The borderline between the diseased and intact ileum, where convinient valves, appear with their thin, delicate outline, can be identified exactly in the mucosal surface. The resection has a "safety margin" of 10 cm. Section of the ascending colon can be performed wherever the surgeon prefers. The ileitis plus right colitis forms require resection of the ileum according to the procedure described and of the right colon, even when the lesions are confined to the caecum. Section and anastomosis must be performed in the initial tract of the transverse colon. The ileitis plus right and left colitis forms call for total colectomy in addition to resection of the ileum, even when the lesions are confined to the transverse colon. The operation is completed with an ileorectal anastomosis constructed on the lower portion of the intraperitoneal rectum (drained by the hypogastric collectors).