On March 2009 a 70yrs old woman was admitted with the feature of severe amyloid cardiomyopathy. Because of a 1st degree AV block and occasional junctional rhythm with R-R max of 6 sc, a pace-maker was immediately placed. Afterwards the episodes the patient had experienced since December 2008 and initially interpreted as ‘‘transient global amnesia’’, stopped. Two years before patient began developing recurrent hemorrhagic bullae of the oral cavity. Moreover since June 2007 the patient had experienced symptoms consistent with palsy of left hypoglossal nerve such as difficulty in speaking, disphagia to solid and right deviation of the tongue. Hemorrhagic bullae were treated as Herpes Simplex infection. Biopsy of a bulla obtained on April 2009 showed amyloid deposition in the vessels. Biopsy at the onset of the bullae would lead to AL amyloidosis diagnosis 2 years earlier. Introduction: It is expected that early diagnosis, obtained when vital organs are not yet damaged, could substantially change the prognosis of AL amyloidosis. From a clinical point of view the possibility of early diagnosis is based on knowledge of all the possible manifestations of the disease, also the less common. Case report: On March 2009, a 70 years old woman was admitted to the Cardiology Unit with leg edema, sudden dyspnea, orthopnea, and hypotension since 2 months before. Echocardiography revealed dramatic biventricular wall thickening with restrictive cardiomyopathy and suggested amyloidosis. A cardiac MRI confirmed the diagnosis of restrictive infiltrative cardiomyopathy compatible with cardiac amyloidosis. Twenty-four hours EKG registration revealed first-degree AV block and occasional junctional rhythm with R-R max 6 sec. A pace maker was immediately implanted. Since December 2008, patient had experienced memory loss and episodes at that time interpreted as ‘transient global amnesia’. A workup of these symptoms was undertaken, and all the laboratory and instrumental tests were negative. After pace maker implantation, the patient did not experience similar episodes; it suggests that the cardiac rhythm disturbances may have a role in the neurological symptoms so far experienced. Serum and urine protein electrophoresis, serum and urine immunofixation did not evidence monoclonal gammopathy. Serum free light chains were also obtained at the time and revealed an excess of lambda light chains (k 19 mg/l, l 110 mg/l, k/l 0. 17), leading to the suspect of AL amyloidosis. A bone marrow biopsy, undertaken in the workup of AL amyloidosis, confirmed the diagnosis. It revealed evidence of a plasma cell dyscrasia with 7–8% plasma cells with lambda predominance and amyloid deposition in the periosteum vessels wall. Past medical history of the patient was unremarkable until April 2007. Since April 2007, about 2 years before the admission to the Cardiology Department, the patient had experienced recurrent hemorrhagic bullae of the oral cavity (Figure 1) that involved hard palate, cheek, and vestibular mucosa. Rarely bullae appeared at the pharyngeal level causing transient dyspnea and dysphonia. Cyclic appearance of bullae became more and more frequent (from a monthly to a weekly frequency). The bullae spontaneously showed rupture and eventually painful afte, 2–6 days lasting. The patient was referred to different specialists for the oral cavity lesions evaluation. Despite negative cultures and serology, bullae were interpreted and treated as Herpes Virus Simplex infection. In June 2007, the patient also developed difficulty in speaking, dysphagia to solid, and noted deviation right deviation of the tongue and progressive hypotrophy of the tongue left side. These features are consistent with left hypoglossal nerve palsy. CNS MRI, EMG, and SSEP of four limbs were negative (Figure 1). Until the admission to the Cardiology Unit on March 2009, the patient had been continuously referred to several specialists in the work-up and treatment of the bullae. In the Cardiology Unit, a biopsy of a new bulla was obtained. Histology showed thickening of sub-epithelial stroma vessels Figure 1. Haemorrhagic bullae at the palate and hypotrophy of the left side of the tongue due to left hypoglossal nerve palsy. 119

The sino-nasal inverted papilloma is a rare benign tumour with certain aggressive features because of frequent relapses and the high probability of malignant degeneration. For these reasons, several studies have been made to evaluate the efficacy of the different courses of treatment, but only afew studies have been carried out to establish the etiology of this tumour, which is still uncertain. Although it is believed that viral infection, chronic inflammation and cigarette smoking can play an important etiological role, it has recently been suggested that occupational risk factors, such as those involved in malignant epithelial sino-nasal cancer (SNC), can also be involved in causing sino-nasal inverted papilloma. A group of 70 patients was examined who have been diagnosed with inverted papilloma from 1991 to 2003; the occupational history, collected via the standardized questionnaire, showed that risk factors like wood and leather dusts, chromium and nickel vapours or fumes and formaldehyde were associated with only 5% of all cases. This proportion is much lower than that established for SNC in several epidemiological studies. Although occupational environmental pollution can be a source of chronic sino-nasal mucosa irritation, on the basis of our results we believe that a causal relationship between exposure to occupational risk factors and inverted papilloma is not likely, differently from the suggestions made in other studies. Consequently, an epidemiological surveillance of inverted papilloma as a "sentinel" tumour, as has been proposed in Italy for SNC, is not considered necessary. Among the possible non-occupational risk factors we observed that 75% of the male patients were smokers and 40% of all patients suffered from chronic sinusitis and sino-nasal polyps. Lastly, among the 70 cases of inverted papilloma, we observed 5 with malignant degeneration.

IN THE CYCLOSPORINE era, short-term results of renal transplantation have dramatically improved; however, the rate of graft loss in the long-term has only marginally improved. Progressive and irreversible decline in renal function suggests a continuous immunologic mechanism leading to chronic rejection (CR) or the participation of nonimmunologic events in the pathogenesis of allograft function deterioration. The risk factors predisposing to CR are not completely known. Clinical variables including donor age, gender, HLA matching, immunosuppressive schedule, and frequency and intensity of acute rejection episodes have been extensively investigated. Morphologic findings have been extensively studied as the most valuable indicators in the diagnosis of acute renal dysfunction such as acute rejection or nephrotoxicity. On the other hand, most authors showed high prevalence of pathologic changes on graft biopsies taken from stable patients. Their value in predicting long-term graft outcome has not completely been established. The knowledge of prognostic value of histologic lesions could facilitate therapeutic decisions and thereby improve the outcome of allograft. We explored the relationship between graft loss for CR and morphologic lesions observed early in well-functioning renal allografts. This study was done at a single centre in a cohort of transplant recipients with long-term follow-up.

Purpose: Adjuvant tamoxifen has been shown to reduce relapse and mortality among node-positive postmenopausal breast cancer patients. The value of adding chemotherapy to tamoxifen is controversial.Patients and Methods: Between July 1986 and April 1993, 1,266 postmenopausal breast cancer patients with node-positive disease were randomly assigned to receive one of four adjuvant therapy regimens: (A) tamoxifen alone for 5 years; (B) tamoxifen plus three courses of early cyclophosphamide, methotrexate, and fluorouracil (CMF) on months 1, 2, and 3; (C) tamoxifen plus delayed single courses of CMF on months 9, 12, and 15; (D) tamoxifen plus early and delayed CMF on months 1, 2, 3, 9, 12, and 15. The two-by-two factorial design allowed two direct comparisons: early CMF (B and D) versus no early CMF (A and C), and delayed CMF (C and D) versus no delayed CMF (A and B). Estrogen receptor (ER) status was known for all patients and was used to stratify the randomization. A total of 1,212 patients (96%) were eligible and assessable. The median followup duration was 60 months.Results: The results of the two-by-two factorial comparison were as follows: (1) early CMF added to tamoxifen significantly improved 5-year disease-free survival (DFS; 64% v 57%; hazards ratio [HR], 0.79; 95% confidence interval [CI], 0.66 to 0.95; P = .01); and (2) delayed CMF added to tamoxifen did not improve DFS (5-year DFS, 61% v 60%; HR, 0.97; 95% CI, 0.81 to 1.17; P = .77). For patients with ER-positive tumors, the addition of CMF, either early or delayed or both, reduced the relative risk of relapse by 22% to 36%. In contrast, for patients with ER-negative tumors, tamoxifen with delayed CMF was associated with a nonsignificant increased risk of relapse (HR, 1.27; 95% CI, 0.92 to 1.76; P = .15).Conclusion: Postmenopausal patients with node-positive breast cancer should be offered combination chemotherapy in addition to tamoxifen. Tamoxifen should not be initiated before CMF, as this might be detrimental, especially for patients with ER-negative tumors. (C) 1997 by American Society of Clinical Oncology.

Purpose: The optimal duration and timing of adjuvant chemotherapy for breast cancer patients remain uncertain and were prospectively studied.Patients and Methods: We randomly assigned 1,554 premenopausal breast cancer patients with node-positive disease in ct 2 x 2 factorial design to receive the following: (A) cyclophosphamide, methotrexate, and fluorouracil for 6 consecutive courses on months 1 to 6 (CMFx6); (B) CMFx6 plus three single courses of reintroduction CMF given on months 9, 12, and 15; (C) CMF for three consecutive courses on months 1 to 3 (CMFx3); or (D) CMFx3 plus three single courses of reintroduction CMF given on months 6, 9, and 12. Accrual was between July 1986 and April 1993. A total of 1,475 patients (95%) were eligible and assessable. The median follow-up duration was 60 months.Results: Patients who received CMFx3 without reintroduction had a 5-year disease-free survival (DFS) rate of 53% compared with 58% for the other three treatment groups (hazards ratio [HR], 1.20; 95% confidence interval [CI], 1.00 to 1.45; P = .04). The increased risk of relapse with CMFx3 was more marked for women aged less than 40 years (308 patients; HR, 1.32; 95% CI, 0.94 to 1.84; P = .11) and for patients with estrogen receptor (ER)-negative tumors (455 patients; HR, 1.45; 95% CI, 1.06 to 2.00; P = .02). Reintroduction chemotherapy provided additional benefit (HR, 0.86; 95% CI, 0.73 to 1.01; P = .07), especially for women greater than or equal to 40 years of age (1,167 patients; HR, 0.82; 95% CI, 0.68 to 0.99; P =.04).Conclusion: Three courses of adjuvant CMF chemotherapy are not sufficient compared with longer duration CMF chemotherapy, especially in younger women and in patients with ER-negative primary tumors. Reintroduction chemotherapy showed some evidence of additional benefit, bur remains investigational. (C) 1996 by American Society of Clinical Oncology.

OBJECTIVETo investigate the immunohistological distribution of beta 2-glycoprotein I (beta 2 GPI) and placental anticoagulant protein I (PAP-I) in normal and pathological placentae of patients with antiphospholipid (aPL) antibody associated recurrent fetal loss. These proteins are 2 natural anticoagulants able to interfere with aPL antibody binding.METHODSPlacentae from 4 patients with primary antiphospholipid antibody syndrome (pAPS), from 2 patients with aPL negative systemic lupus erythematosus (SLE) and from 7 healthy women were studied. Cryostatic placental sections were tested by indirect immunofluorescence using polyclonal anti-PAP-I and anti-beta 2GPI antisera as well as purified IgG and anti-beta 2GPI monoclonal antibody. The same tissue sections were also tested by direct immunofluorescence with FITC-F(ab)2 goat antihuman IgG.RESULTSWe found that (a) the placental distribution of PAP-I was comparable in normal and pathological specimens; (b) on the contrary, increased beta 2GPI deposition was present on the trophoblast surfaces of placentae obtained from patients with persistent raised titers of aPL antibodies. Comparable IgG deposition on villi surface was also found in aPL positive but not in control placentae.CONCLUSIONOur data are consistent with the hypothesis that high titer aPL binds to a beta 2GPI phospholipid complex in placentae of women with recurrent fetal loss but that a quantitative deficiency of PAP-I does not play a pathogenetic role in aPL associated fetal loss.

A hospital-based case-control study was carried out to investigate the association between ANCA positive rapidly progressive glomerulonephritis (RPGN) and occupational exposure to silica dust. All ANCA positive male patients admitted to the Department of Nephrology of the University of Brescia between 1987 and 1992 were enrolled in the study as cases. The controls were pts of the same age, admitted at the Department immediately before or after the cases, affected by other renal diseases. Seven of the 16 cases and one of the 32 controls, had a positive history for jobs exposing to silica dust (relative risk 14; 95% C.I.: 1.7-113.8, p < 0.001). ANCA pattern was p-ANCA with anti-MPO antibodies in 6/7 of exposed pts. The review of renal histology showed a distinctive glomerular lesion consisting in peripheral nodular areas of glomerular sclerosis, in addition to the crescentic necrotizing glomerulonephritis, in 3/6 silica exposed pts, but in none of the unexposed pts.

Six hundred and eighty-four primary breast cancers from the International (Ludwig) Breast Cancer Study Group (IBCSG) were studied for Helix pomatia lectin (HPA) binding. There was a weak correlation between lymph node-positive and HPA positive (P = 0.04). In our series there was a large advantage in disease-free survival (DFS) and overall survival (OS) for node-negative patients (P < 0.0001 DFS and OS). However, there was no such advantage for HPA-negative patients (P = 0.23 DFS and P = 0.32 OS). We conclude that in this randomised patient group HPA is of no clinical predictive value.

Placental bed biopsies were obtained during caesarean section from normal, pre-eclamptic and hypertensive pregnancies. Of the 14 biopsies from normal pregnancies 13 showed normal vascular physiological changes in the decidua and in the myometrium. Biopsies from 24 pregnancies complicated by pre-eclampsia showed acute atherosis in 18 and physiological changes limited to the decidua in six; none had normal physiological changes. Biopsies from five hypertensive patients showed all three types of histological changes. The mean birthweight centile was lower in the group with atherosis than in the group with limited and the group with normal physiological changes.