Terlipressin infusion induces ischemia of breast skin in a cirrothic patient with hepatorenal syndrome.

We report a case of a 65-year-old woman with hepatitis C virus-related decompensated cirrhosis with hepatorenal syndrome, treated by high dose of terlipressin. Few hours after the highest dose was started, the patient complained burning pain in breasts, followed by the development of extensive bilateral cyanosis of breast's skin. When terlipressin was immediately stopped, pain and skin cyanosis rapidly disappeared. The peculiarity of our case is that cyanosis did not develop in common peripheral sites (e.g. fingers, toes, etc.) but in an atypical area, as skin of the breasts. Probably, this particular behaviour could be explained by the anatomical position of her large size breasts, that resulting as an extremely sloping and stretching region thus filling the maximum effect of gravity.

[Long-term effects of cyclic therapy with iloprost in systemic sclerosis]. / Effetti a lungo termine della terapia ciclica con iloprost nella sclerosi sistemica.

OBJECTIVE: To assess the long-term effects of cyclic infusion of iloprost, a derivative of prostacyclin, on Raynaud's phenomenon-related symptoms and ischemic ulcers in patients with Systemic Sclerosis (SSc). METHODS: A retrospective analysis of prospectively collected parameters in 59 consecutive SSc patients, followed at one institution, who were treated for a median time of 52 months with iloprost for severe Raynaud's phenomenon and ischemic ulcers. RESULTS: Among the 50 patients with ischemic ulcers at the start of therapy, 35 (70%) did not show lesions at the last observation. Despite therapy, four patients underwent amputations (two of forefoot, two of finger distal phalanges). Compared to the pre-treatment point, we observed: decrease of the Raynaud's phenomenon VAS (p<0.001), and, in patients with diffuse cutaneous involvement, of the modified Rodnan skin thickness score (p=0.002). The Health Assessment Questionnaire was not significantly improved. CONCLUSION: Treatment with cyclic iloprost can control Raynaud's phenomenon-related symptoms and ischemic ulcers in the large majority of patients with SSc. However, a disease-modifying effect of this therapy could not be demonstrated.

Disease-modifying effects of long-term cyclic iloprost therapy in systemic sclerosis. A retrospective analysis and comparison with a control group.

OBJECTIVE: To evaluate the role of iloprost, a derivative of prostacyclin, as a possible disease-modifying agent for systemic sclerosis (SSc). METHODS: Fifty-six consecutive SSc patients treated for a median period of 4 years with cyclic infusions of iloprost for severe Raynaud's phenomenon and ischemic ulcers were compared with 56 control patients matched for age, sex, disease subset and duration. Control patients were also similar to the iloprost group with regard to autoantibody status, the presence of major disease-related organ manifestations at baseline, and the use of other treatments. The evolution of lung function test results, the frequency of major disease-specific complications and the survival of the cohorts were the objects of this analysis. RESULTS: No significant difference was observed between the two groups with regard to changes in lung function tests over time, or the number of patients who presented with the onset of active interstitial lung disease, pulmonary arterial hypertension or scleroderma renal crisis. Survival did not differ between the two groups. CONCLUSION: The evolution of lung function test results, the frequency of major disease-specific complications, and survival did not differ significantly between SSc patients treated with cyclic iloprost and a group of patients matched for sex, age, and disease subset and duration. However, no cases of severe pulmonary arterial hypertension were observed in the patients treated with iloprost, suggesting that studies focusing on the possible preventive action of iloprost on the progression of SSc- associated mild pulmonary arterial hypertension would be warranted.

Intravenous cyclophosphamide for interstitial lung disease associated to systemic sclerosis: results with an 18-month long protocol including a maintenance phase.

OBJECTIVE: Cyclophosphamide (CYC) is generally considered the most promising agent available today for systemic sclerosis (SSc)-related interstitial lung disease (ILD). However, the optimal dosage and length of treatment are still undetermined. Our objective was to evaluate the effect of an 18-month long protocol with intravenous (iv) CYC. METHODS: In a single-centre, prospective, observational study, 13 patients with SSc and active alveolitis were given 8 iv pulses in a 6-months period (CYC 750 mg + 6-methylprednisolone 125 mg every three weeks), as an induction therapy. Patients received maintenance therapy with further cycles at 4 (3 pulses), 6 (3 pulses) and 9 weeks (3 pulses) interval. Total CYC dosage was 12.75 g in an 18-month period. End-points were modifications of lung function test (LFT). RESULTS: During the first 6 months of treatment with CYC an increase in Forced Vital Capacity (FVC; p = 0.005) and in diffusion lung capacity for carbon monoxide (DLCO; p = 0.10) was observed; during the maintenance therapy, there was a stabilization in FVC and a mild, non significant decline in DLCO. Treatment was well tolerated. CONCLUSION: iv CYC can induce an initial improvement in LFT (particularly, in FVC) in the first six months, but no further improvement was observed during the maintenance phase.

Effects of the combined treatment with thalidomide, megestrol and interleukine-2 in cirrhotic patients with advanced hepatocellular carcinoma. A pilot study.

BACKGROUND: Thalidomide, an anti-angiogenic agent, does not have a good therapeutic effect for advanced hepatocellular carcinoma when used alone. Megestrol and interleukin-2 have been proposed as a palliative treatment for hepatocellular carcinoma. AIMS.: We assessed the effectiveness/safety of a combined therapy with thalidomide+megestrol+interleukin-2 in cirrhotic patients with advanced hepatocellular carcinoma. PATIENTS AND METHODS: Nine cirrhotic patients with advanced hepatocellular carcinoma received oral megestrol (160 mg/day) and thalidomide (from 50 mg/day to the maximal tolerated dose). Four patients also received subcutaneous interleukin-2 (1 million U/day for 21 days/month). RESULTS: The maximal tolerated dose of thalidomide was 150 mg/day. All patients complained of sedation and other neurological or digestive adverse effects. In all but one patient the adverse effects disappeared after thalidomide withdrawal or dose reduction. Interleukin-2 administration caused a flu-like syndrome and a reaction at the injection site. During treatment, alpha-fetoprotein increased in six patients, remained stable in two and decreased in one. Eight patients showed tumour progression and one had a stable disease. Eight patients died. The median survival was 9.9 (range 2.6-18.6) months. CONCLUSION: In cirrhotic patients, the combined treatment with thalidomide+megestrol (+/-interleukin-2) does not control hepatocellular carcinoma growth, possibly due to the low tolerance to thalidomide and interleukin-2 preventing the use of appropriate dosages.

Evidence of oxidative imbalance in long-term liver transplant patients.

BACKGROUND: Oxidative stress in patients undergoing liver transplantation results both from the pre-existing cirrhosis and ischaemia-reperfusion injury related to surgery. Previous studies have provided information limited to the immediate post-operative period. It remains to be established whether this oxidative imbalance is reversed in a longer time. AIM, METHODS AND PATIENTS: This study aimed to compare plasma concentrations of thiobarbituric acid-reactant substances and alpha-tocopherol in 20 cirrhotic patients before liver transplantation and 22 patients in whom transplant had been carried out at least 6 months previously. Thirty healthy age and sex-matched volunteers served as controls (cross-sectional study). Five patients were evaluated before and after liver transplantation (longitudinal study). RESULTS AND CONCLUSIONS: Pre-transplant patients showed greater thiobarbituric acid-reactant substances and lower alpha-tocopherol levels than controls. Transplanted patients presented lower thiobarbituric acid-reactant substances and greater alpha-tocopherol levels than cirrhotic patients without reaching, however, the levels observed in controls. No correlations were found between oxidative parameters and liver tests. Hypertransaminasaemia, liver disease recurrence, and rejection episodes did not significantly influence the oxidative parameters. In the longitudinal study, transplantation induced a significant decrease in plasma thiobarbituric acid-reactant substances and a rise in alpha-tocopherol. Although a long-term improvement in the oxidative injury observed in cirrhotic patients occurs after liver transplantation, mild oxidative stress persists even in successfully transplanted patients.

Systemic sclerosis therapy with iloprost: a prospective observational study of 30 patients treated for a median of 3 years.

Iloprost is useful in the short-term treatment of severe Raynaud's phenomenon and ischaemic ulcers in patients with systemic sclerosis (SSc), but its long-term effects are largely unknown. The aim of this study was to report long-term outcome (median follow-up 36 months) in a prospective observational study of a cohort of 30 consecutive patients with SSc who received iloprost therapy with maintenance infusions every 3 weeks after an initial cycle of 5 consecutive days. At the end of the observation, compared to the pretreatment point, we observed complete healing of digital ulcers in 19/21 patients (90%), a decrease of the Raynaud's phenomenon visual analogue score from 10/10 (25th-75th percentile 7-10) to 5/10 (4-6.75) ( P <0.001) and, in patients with diffuse cutaneous involvement, of the modified Rodnan skin thickness score from 25.5 (16.5-31.5) to 16 (13.5-20) ( P = 0.02), minimal improvement of the Health Assessment Questionnaire from 0.87 (0.68-1.37) to 0.75 (0.62-1.25), which was neither statistically nor clinically significant. The forced vital capacity was not significantly changed, but the diffusion capacity corrected for the alveolar volume decreased from 71% (54-76.7) of the expected value to 62% (51.5-71) ( P = 0.02). In one patient with limited SSc a positive effect on pulmonary hypertension was observed. Six patients, after a median of 25 months of treatment and healing of digital ulcers, discontinued the therapy; after a median of 10 months ulcers did not recur in five of these six. Other reasons for discontinuation were: tolerability (1), disease progression (normotensive renal crisis: 1), and death due to intracranial haemorrhage (1). This same patient had previously suffered a central retinal vein thrombosis. In conclusion, long-term therapy with iloprost in patients with SSc has a durable effectiveness on ischaemic ulcers and Raynaud's phenomenon, but it is not possible to conclude that the natural history of the disease was modified.

[Update on paraneoplastic hypercalcemia. Our experience in the treatment of hypercalcemic states of patients with advanced breast carcinoma]. / Attualità in tema di ipercalcemia paraneoplastica. La nostra esperienza nel trattamento degli stati ipercalcemici delle pazienti con carcinoma mammario avanzato.

The treatment of hypercalcemia of malignancy is troublesome. Personal experience with breast cancer associated hypercalcemia is presented. Eight patients were hydrated with intravenous administration of saline solution containing high doses of salmon calcitonin and subsequently six were treated with antiblastic polychemotherapy. Calcium level fell to normal in all patients. Hypercalcemia, with or without evidence of metastatic bone disease, may be caused by the production of humoral substance by tumoral tissue. In our experience the first therapeutic stage is the infusion of saline solution containing high doses of calcitonin, while the elective treatment is antiblastic polychemotherapy which, acting on tumour growth, may inhibit the release of humoral mediators of hypercalcemia causing a slower but stable reduction in serum calcium level.

"Torsade de pointes" during amiodarone infusion in a cirrhotic woman with a prolonged QT interval.

We describe an interesting case of a woman with decompensated cirrhosis, ischaemic heart disease and prolonged QT interval, who developed a new-onset atrial fibrillation. During amiodarone infusion a torsade de pointes occurred, which was immediately converted to sinus rhythm by synchronized cardioversion. A new episode of atrial fibrillation was treated with infusion of a beta-blocker (metoprolol) that restored sinus rhythm and normalized the QT interval. Delayed repolarization, frequently observed in ischaemic heart disease, cirrhosis and pro-arrhythmic drugs administration, represents the background for the development of torsade de pointes. Our report underlines that the potential harmfulness of a prolonged QT interval in cirrhotic patients is currently not perceived in its entirety, so that various categories of drugs affecting ventricular repolarization are rather thoughtlessly used in clinical practice without monitoring the QT interval. Thus, amiodarone should be avoided, if possible, or used with extreme care in arrhythmic patients with advanced liver disease. Moreover, beta-blockers may be considered the first-line treatment for rate-control during supraventricular tachyarrhythmias in cirrhotic patients with delayed repolarization.

Human herpesvirus-8-related Kaposi's sarcoma after liver transplantation successfully treated with cidofovir and liposomal daunorubicin.

The iatrogenic form of Kaposi's sarcoma (KS) is typically observed among transplant recipients, and the most appropriate therapeutic approach (usually including reduction of immunosuppression, specific chemotherapy, and/or administration of antiviral agents against human herpes virus-8) is still controversial. Available experiences on the effect of the anti-herpes viruses drug cidofovir provide conflicting results. Herein, we report the clinical, histological, and virological features of a liver transplant recipient successfully treated with a combined therapy of cidofovir and liposomal daunorubicin, associated with a reduction of the immunosuppressive regimen, for an advanced cutaneous and visceral KS.

5-Fluorouracil and high-dose folinic acid as salvage treatment of advanced breast cancer: an update.

We report an update of our results of a trial of high-dose folinic acid (HDFA) and 5-fluorouracil (5-FU) in advanced breast cancer. Thirty-eight patients with advanced and mainly refractory breast cancer were treated with the following regimen: HDFA (200 mg/m2/day) and 5-FU (340, 370, 400 mg/m2/day) given immediately afterwards, for 5 consecutive days every 4 weeks. Of 36 evaluable patients, 3 achieved complete remission (8%) and 13 partial remission (36%) for an overall response rate of 44%, while 11 patients (30%) had stable disease. Thirteen out of sixteen responders (85%) were pretreated with some 5-FU-containing regimens. The median duration of response was 9.6+ months, the median survival for responders and for patients with stable or progressive disease was 19.9+, 18.8+ and 9 months, respectively. The overall toxicity was acceptable: while hematological toxicity was very mild, oral mucositis, diarrhea and conjunctivitis were major side effects. These results seem very promising and deserve further evaluation.

Treatment of advanced colorectal and gastric cancer with cisplatinum and 5-fluorouracil. A pilot study.

Eighteen patients with measurable advanced colorectal cancer and four with metastatic gastric cancer were treated with cisplatin 100 mg/m2 day 1 and 5-fluorouracil (5-FU) 1000 mg/m2 administered over 6 h i.v. infusion from days 2 to 5 every 21 to 28 days. Five out of 15 fully evaluable patients with colorectal cancer experienced a partial response (33%) while amongst the three evaluable patients with gastric cancer one complete and one partial remission were achieved. Both hematological and non-hematological side-effects were mild. Our preliminary results seem quite interesting and deserve further evaluation.

Endogenous heparin-like activity detected by anti-Xa assay in infected cirrhotic and non-cirrhotic patients.

BACKGROUND: Bacterial infections have been proposed as a trigger for portal hypertensive bleeding in cirrhotic patients. Endogenous low molecular weight heparinoids have been previously detected in vitro by heparinase-modified thromboelastography, but it is not known what type of heparinoids they are. The aim of this study was to assay anti-Xa concentrations to detect heparin activity in infected cirrhotics in vivo. METHODS: We evaluated 30 cirrhotic patients (15 with bacterial infection, 15 not infected) and 9 non-cirrhotic patients with bacterial infection. The anti-Xa assay was performed at the start of infection in all patients and after resolution of infection in 8 cirrhotics (5 to 10 days after starting antibiotics); thromboelastography (native and heparinase I-modified TEG) was performed in a subgroup of 11 cirrhotic patients with infection, 8 cirrhotics without infection and 8 non-cirrhotics with infection. RESULTS: Anti-Xa activity was detected in 9 of the 15 infected cirrhotics (60%) and only in 1 of 15 non-infected cirrhotics (6.7%) (P < 0.01). In the infected cirrhotic patients, a heparinase effect was shown in the heparinase I-modified TEG: k time (P < 0.01), alpha-angle (P < 0.01) and r time (P = 0.05), with no effect in the non-infected cirrhotics. Four of 9 (44%) infected non-cirrhotics were positive with the anti-Xa assay. CONCLUSION: In cirrhotic patients, bacterial infections modify haemostasis by producing endogenous heparin-like substances which can inhibit the activated clotting factor X (factor Xa). In infected non-cirrhotics, anti-Xa activity can also be found.

Central nervous system involvement in systemic lupus erythematosus: a new therapeutic approach with intrathecal dexamethasone and methotrexate.

In systemic lupus erythematosus (SLE), neurological involvement has been reported to occur with frequencies ranging from 14% (severe cases) to 83% (mild forms included). In spite of early diagnosis and aggressive treatment, neuropsychiatric SLE may represent a serious problem of management. We describe three cases, one with acute transverse myelitis, one with hemiparesis, and one with signs of focal and diffuse cerebral dysfunction, in whom improvement following intrathecal therapy with methotrexate and dexamethasone was observed.