Long-term outcomes of direct acting antivirals in post-transplant advanced hepatitis C virus recurrence and fibrosing cholestatic hepatitis.

Long-term functional outcomes of sofosbuvir-based antiviral treatment were evaluated in a cohort study involving 16 Italian centres within the international compassionate use programme for post-transplant hepatitis C virus (HCV) recurrence. Seventy-three patients with cirrhosis (n=52) or fibrosing cholestatic hepatitis (FCH, n=21) received 24-week sofosbuvir with ribavirin±pegylated interferon or interferon-free sofosbuvir-based regimen with daclatasvir/simeprevir+ribavirin. The patients were observed for a median time of 103 (82-112) weeks. Twelve of 73 (16.4%) died (10 non-FCH, 2 FCH) and two underwent re-LT. Sustained virological response was achieved in 46 of 66 (69.7%): 31 of 47 (66%) non-FCH and 15 of 19 (79%) FCH patients. All relapsers were successfully retreated. Comparing the data of baseline with last follow-up, MELD and Child-Turcotte-Pugh scores improved both in non-FCH (15.3±6.5 vs 10.5±3.8, P<.0001 and 8.4±2.1 vs 5.7±1.3, P<.0001, respectively) and FCH (17.3±5.9 vs 10.1±2.8, P=.001 and 8.2±1.6 vs 5.5±1, P=.001, respectively). Short-treatment mortality was higher in patients with baseline MELD≥25 than in those with MELD<25 (42.9% vs 4.8%, P=.011). Long-term mortality was 53.3% among patients with baseline MELD≥20 and 7.5% among those with MELD<20 (P<.0001). Among deceased patients 75% were Child-Turcotte-Pugh class C at baseline, while among survivors 83.9% were class A or B (P<.0001). Direct acting antivirals-based treatments for severe post-transplant hepatitis C recurrence, comprising fibrosing cholestatic hepatitis, significantly improve liver function, even without viral clearance and permit an excellent long-term survival. The setting of severe HCV recurrence may require the identification of "too-sick-to-treat patients" to avoid futile treatments.

Smac127 Has Proapoptotic and Anti-Inflammatory Effects on Rheumatoid Arthritis Fibroblast-Like Synoviocytes.

Rheumatoid arthritis (RA) is characterized by synovial inflammation and hyperplasia. Fibroblast-like synoviocytes (FLSs) are apoptosis-resistant and contribute to the pathogenesis of RA by producing cytokines and proteolytic enzymes, which degrade the extracellular matrix. We evaluated the proapoptotic and anti-inflammatory activity of the small molecule Smac127 on RA-FLSs cultured in synovial fluid (SF), in order to reproduce the physiopathological environmental characteristic of RA joints. In this context, Smac127 induces apoptosis by inhibiting apoptosis proteins (IAPs). This inhibition activates caspase 3 and restores the apoptotic pathway. In addition, Smac127 induces a significant inhibition of the secretion of IL-15 and IL-6, stimulation of pannus formation, and damage of bone and cartilage in RA. Also the secretion of the anti-inflammatory cytokine IL-10 is dramatically increased in the presence of Smac127. The cartilage destruction in RA patients is partly mediated by metalloproteinases; here we show that the MMP-1 production by fibroblasts cultured in SF is significantly antagonized by Smac127. Conversely, this molecule has no significant effects on RANKL and OPG production. Our observations demonstrate that Smac127 has beneficial regulatory effects on inflammatory state of RA-FLSs and suggest a potential use of Smac127 for the control of inflammation and disease progression in RA.

Statin therapy: improving survival in patients with hepatocellular carcinoma and portal hypertension is possible?

Statins are generally known for their lipid-lowering properties and protection against cardiovascular events. However, growing evidence suggests that statins are a promising treatment for patients with chronic liver disease. Specifically, there is data supporting their role in reducing portal pressure and having a chemopreventive effect on hepatocellular carcinoma (HCC). Treatment options for HCC remain limited with portal hypertension (PH), thus statins could represent an inexpensive alternative, increasing survival of patients with HCC and PH. These drugs cannot be considered standard of care without a cardiac-metabolic indication to prescription in this patient group, although the potential beneficial effect should be indication for prompt use whenever considered appropriate. Our aim is to review the effects of statins on PH and on HCC, both in the pre-clinical and clinical setting in literature, discussing safety issues and limitations to the current body of evidence.

Is surgical restaging indicated in apparent stage IA pure ovarian dysgerminoma? The MITO group retrospective experience.

OBJECTIVE: Conservative surgery followed by platinum-based chemotherapy is considered the standard approach for pure ovarian dysgerminoma (POD), except for correctly staged IA patients. The aim of study was to evaluate the outcome of IA POD patients with incomplete surgical staging in order to define the proper management. METHODS: Data concerning primary treatment and recurrence were reviewed for 26 patients with stage IA POD treated in MITO (Multicenter Italian Trials in Ovarian Cancer) centers. RESULTS: Median age was 22.5years. Primary surgery was fertility sparing for 17 patients (65.4%) and radical surgery was performed in 9 patients due to older age or gonadal dysgenesis. Only five patients (19.2%) had complete surgical staging; 38.5% had lymph node dissection, 46.2% had peritoneal biopsies and/or omentectomy and 65.4% had peritoneal washing. Seven patients received adjuvant chemotherapy. Overall recurrence rate was 11.5%: all recurrences occurred in the group submitted to incomplete staging procedure. No patients treated with adjuvant chemotherapy relapsed. One patient had pelvic recurrence, one patient relapsed in the abdomino-pelvic peritoneum and lymph nodes and the third patient showed a peritoneum, lymph nodal and residual ovary relapse. All patients with recurrence were cured by salvage therapy: 2 patients were treated with surgery plus chemotherapy and one only with chemotherapy. After a median follow-up of 100months all patients are alive without evidence of disease. Six patients opted for conception and delivered healthy infants, two with IVF with donor oocyte. CONCLUSIONS: IA POD prognosis is excellent. Conservative surgery with a complete surgical staging is the gold standard. Patients with incomplete staging could undergo surgical restaging or surveillance. Chemotherapy should be reserved to relapse with excellent chances of therapeutic success.

Evaluation of pemetrexed (Alimta, LY231514) as second-line chemotherapy in persistent or recurrent carcinoma of the cervix: the CERVIX 1 study of the MITO (Multicentre Italian Trials in Ovarian Cancer and Gynecologic Malignancies) Group.

BACKGROUND: The objective of the study was to estimate the antitumor activity of pemetrexed in patients with advanced/recurrent carcinoma of the cervix and to determine the nature and degree of toxicity. METHODS: A multicenter phase II trial was conducted by the Multicentre Italian Trials in Ovarian Cancer and Gynecologic Malignancies (MITO) Group. Patients with advanced/recurrent measurable carcinoma of the cervix that had failed one prior chemotherapy regimen in association or not with radiotherapy were treated with pemetrexed at a dose of 500 mg/m(2) every 21 days. All the patients had a measurable lesion according to RECIST criteria in a not previously irradiated field. RESULTS: From November 2006 to September 2008, 43 patients were entered by seven member institutions of the MITO-Group. A total of 164 cycles (median 2, range 1-9) were administered. The treatment was well tolerated. More serious toxic effects (grades 3 and 4) included leukopenia in 27.9% and neutropenia in 30.2% of patients. No treatment-related deaths were reported. Six patients (13.9%) had partial responses (at least a 30% decrease in the sum of longest diameter of target lesions taking as reference the baseline sum longest diameter) with a median response of 7 weeks (range 3-27). Twenty-three patients (53.4%) had stable disease (less than a 50% reduction and less than a 25% increase in the sum of the products of two perpendicular diameters of all measured lesions and the appearance of no new lesions) and fourteen (32.5%) patients had progressive disease. Median progression-free survival was 10 weeks and overall survival was 35 weeks. CONCLUSION: Pemetrexed showed moderate activity against advanced/recurrent cervical cancer that had failed prior chemotherapy.

Is adjuvant chemotherapy indicated in stage I pure immature ovarian teratoma (IT)? A multicentre Italian trial in ovarian cancer (MITO-9).

OBJECTIVE: Conservative surgery followed by platinum-based chemotherapy is considered the standard approach for stage I immature ovarian teratoma (IT), except for stage IA G1. Nevertheless the use of chemotherapy in stage IA G2-3 and IB-IC is controversial. The aim of this study was to evaluate the outcome of patients with IT in order to define the role of chemotherapy in stage I disease. METHODS: Twenty-eight patients with stage I IT treated in MITO centers were retrospectively reviewed. Grade, stage, age, surgical and postoperative treatment were analyzed using χ(2) test and T test looking for association with recurrence. RESULTS: Median age was 25.5. Twenty-four patients underwent fertility-sparing surgery. FIGO stages were 19 IA, 2 IB, and 7 IC. Nine patients had grade 1 tumor, 12 grade 2, and 7 grade 3. Nine patients received adjuvant chemotherapy. Overall recurrence rate was 21.4% (2 in chemotherapy group and 4 in the group without treatment). No patients with G1 had recurrence, whereas 25% of G2 and 42.9% of G3 relapsed. Recurrence rate was not significantly different according to stage, grade or adjuvant chemotherapy, whereas it was greater in the group not operated in a MITO center, not staged and of age lower than 20 years, with statistical significance. At recurrence 4 patients presenting with mature teratoma were treated with surgery alone, whereas 2 recurring with IT were treated with surgery plus chemotherapy. After a median follow-up of 59 months all patients are NED. CONCLUSIONS: Our study suggests that chemotherapy may be withheld for primary therapy and utilized only for recurrence.

Positron emission tomography/computed tomography introduction in the clinical management of patients with suspected recurrence of ovarian cancer: a cost-effectiveness analysis.

Aim of this study was to evaluate the economic impact of the introduction of positron emission tomography/computed tomography (PET/CT) in the early detection of recurrent ovarian cancer through a cost-effectiveness analysis of different diagnostic strategies. Thirty-two consecutive patients with suspected ovarian cancer recurrence, studied by both contrast enhanced abdominal CT and PET/CT, were retrospectively included in the study. Three different diagnostic strategies were evaluated and compared: (1) CT only or baseline strategy; (2) PET/CT for negative CT or strategy A; (3) PET/CT for All or strategy B. For each one, expected costs, avoided surgery and incremental cost-effectiveness ratio (ICER) were calculated to identify the most cost-effective strategy. The number of positive patients increased from baseline strategy (20/32) to strategy A and B (30/32 and 29/32 respectively). Positron emission tomography/computed tomography reoriented physician choice in 31% and 62% of patients (strategies A and B respectively). Strategy A is dominated by strategy B, which is more expensive (2909 euro vs. 2958 euro), but also more effective (3 cases of surgery avoided) and presents an ICER of 226.77 euro per surgery avoided (range: 49.50-433.00 euro). Positron emission tomography/computed tomography introduction in this population is cost-effective and allowed to redirect the clinical management of patients towards more appropriate therapeutic choices.

Prevention strategies in palmar-plantar erythrodysesthesia onset: the role of regional cooling.

OBJECTIVE: Palmar-plantar erythrodysesthesia (PPE) is a characteristic cutaneous toxicity associated with pegylated liposomal doxirubicin (PLD). Different therapies have been proposed to alleviate PPE onset. We performed a prospective study to evaluate preventive strategies to reduce PPE incidence in patients treated for gynecologic cancers. METHODS: Fifty-three patients were treated from 2001 to 2006 with PLD as single agent therapy or in combination with carboplatin or paclitaxel. PLD dosages were in the range of 30-50 mg/m2 every 21-28 days. All patients received premedication with dexamethasone and pyridoxine. Twenty-eight patients received application of ice packs on extremities during PLD infusion. RESULTS: PPE was observed in 11 patients (20.8%). PLD administration as single agent or in combination and schedule of PLD therapy did not affect PPE incidence. A significant reduction in PPE onset was observed if PLD dosage was 30-35 mg/m2 (p=0.03) and when patients were submitted to regional cooling protocol (p=0.0097). CONCLUSIONS: The use of ice packs around wrists and ankles is a simple and well tolerated prevention strategy and its efficacy is demonstrated in this study.

Paracetamol/Tramadol association: the easy solution for mild-moderate pain.

Some authors have proposed an updating of the therapeutic recommendations for some kinds of pain, such as musculoskeletal, post-traumatic and post-surgical pain for which a multimodal approach is being increasingly considered. With regard to this, an association of analgesics belonging to different pharmacological classes becomes an important option, given that analgesic efficacy can be ensured using lower dosages of single components, improving the tolerability of the drugs. The fixed combination of paracetamol (325 mg) and tramadol (37.5 mg) has a precisely dose ratio to obtain an additive analgesic effect, improving both the analgesic efficacy, which is more stronger and complete, and the duration of the action, guaranteeing a quick analgesic effect over time. A wide international literature exists for this association. This review considers particularly 15 studies. In nine of them, all double-blind, the duration of treatment was 1-10 days and, in total, 2 537 patients were admitted, affected by acute painful flares of chronic-degenerative pathologies, trauma or subjected to surgery. The mean daily dose of paracetamol/tramadol most frequently used was 4.3-4.5 tablets/day. Rigorous studies were conducted also for chronic pain; in the 6 studies considered the duration of treatment was 4-13 weeks and a total of 1 890 patients, affected by chronic musculoskeletal pain, were admitted. The mean daily dose of paracetamol/tramadol was between 3.5 and 4.2 tablets/day, showing itself to be constant and independent of the disease considered. In conclusion, the fixed association paracetamol/tramadol is a new therapeutic option, particularly useful in mild-moderate pain where paracetamol is inadequate.

The prevention of analgesic opioids abuse: expert opinion.

Opioids are drugs of reference for the treatment of moderate to severe pain. Their proper use and a periodic assessment of the patient are crucial to prevent misuse. A multidisciplinary group suggests strategies for all stakeholders involved in the management of pain and suggests the importance of the doctor-patient relationship.

The validity of predicted body fat percentage from body mass index and from impedance in samples of five European populations.

OBJECTIVES: To test and compare the validity of a body mass index (BMI)-based prediction equation and an impedance-based prediction equation for body fat percentage among various European population groups. DESIGN: Cross-sectional observational study. SETTINGS: The study was performed in five different European centres: Maastricht and Wageningen (The Netherlands), Milan and Rome (Italy) and Tampere (Finland), where body composition studies are routinely performed. SUBJECTS: A total of 234 females and 182 males, aged 18-70 y, BMI 17.0-41.9 kg/m(2). METHODS: The reference method for body fat percentage (BF%(REF)) was either dual-energy X-ray absorptiometry (DXA) or densitometry (underwater weighing). Body fat percentage (BF%) was also predicted from BMI, age and sex (BF%(BMI)) or with a hand-held impedance analyser that uses in addition to arm impedance weight, height, age and sex as predictors (BF%(IMP)). RESULTS: The overall mean (+/-s.e.) bias (measured minus predicted) for BF%(BMI) was 0.2+/-0.3 (NS) and-0.7+/-0.3 (NS) in females and males, respectively. The bias of BF%(IMP) was 0.2+/-0.2 (NS) and 1.0+/-0.4 (P<0.01) for females and males, respectively. There were significant differences in biases among the centres. The biases were correlated with level of BF% and with age. After correction for differences in age and BF% between the centres the bias of BF%(BMI) was not significantly different from zero in each centre and was not different among the centres anymore. The bias of BF%(IMP) decreased after correction and was significant from zero and significant from the other centres only in males from Tampere. Generally, individual biases can be high, leading to a considerable misclassification of obesity. The individual misclassification was generally higher with the BMI-based prediction. CONCLUSIONS: The prediction formulas give generally good estimates of BF% on a group level in the five population samples, except for the males from Tampere. More comparative studies should be conducted to get better insight in the generalisation of prediction methods and formulas. Individual results and classifications have to be interpreted with caution.

Indirect calorimetry and nutritional problems in clinical practice.

Indirect calorimetry is a simple and affordable tool for measuring energy expenditure and for quantifying the utilization of macronutrients. Its use is becoming increasingly widespread, but it is necessary to know its methodological features and its theoretical and practical limitations. Indirect calorimetry measures the rate of resting energy expenditure (REE), the major component of the total daily energy expenditure. Thus, indirect calorimetry reliably estimates the individual energy needs. Coupling the measurement of body composition to that of REE expands the diagnostic potential of indirect calorimetry. Once the lean and fat compartments have been measured, it is possible to establish on the basis of REE whether an individual is hyper- or hypometabolic. The evaluation of substrate oxidation by indirect calorimetry is subject to more severe theoretical constraints, because certain metabolic assumptions must be made. The clinical applications are practically unlimited. In the critically ill, a major goal is to maintain energy balance during the hypermetabolic response following trauma. The REE measurement is valuable from the diagnostic standpoint, because it recognizes discrepancies from the expected time-course of hypermetabolism, for example signaling a potentially catastrophic hypometabolic response. REE is also indispensable for providing correct nutritional support because both hyper- and undernutrition lead to increased mortality. In young or elderly patients, in whom energy consumption may be very different from that predicted from equations based on anthropometric measures, indirect calorimetry is particularly useful.

Identification of high risk patients with endometrial carcinoma. Prognostic assessment of endometrial cancer.

OBJECTIVES: To verify the importance of DNA ploidy on clinical outcome in endometrial carcinoma and to investigate whether the prognostic information obtained by this variable is independent from other clinical-pathologic features. MATERIALS AND METHODS: Univariate and multivariate analysis of clinical and pathologic prognostic factors obtained from 203 consecutive cases of endometrial cancer, that had been surgically treated in our hospital, were performed. RESULTS: Significant prognostic factors according to the Kaplan-Meier method were age at the time of diagnosis, grade of differentiation, peritoneal cytology, node involvement, vascular invasion, myometrial infiltration and ploidy. At multivariate analysis only DNA ploidy resulted to be an independent variable. CONCLUSIONS: In our analysis DNA content is the only parameter which preserved prognostic significance in multivariate analysis.

Comparison of optimal cytoreduction rates in emergency versus non-emergency admissions for advanced ovarian cancer: a multi-institutional study.

AIMS: to investigate whether first referral to the Emergency Department (ED) of a General Hospital is an independent risk-factor for suboptimal debulking compared to a similar population electively admitted to cytoreductive surgery, in a cohort of 307 AOC patients. METHODS: this is a multicentre case-control study, analyzing a cohort of 307 AOC patients treated at San Raffaele Hospital of Milan (111 Center A) and Gemelli Hospital of Rome (196 Center B) between January 2006/2008 and December 2010. Women are classified as patients admitted to the Hospital from ED (Cases) and out-patients (Controls). RESULTS: At univariate analysis, Cases significantly differ from Controls in terms of worse ECOG PS, larger ascites, pleuric effusion and peritoneal carcinomatosis. The rate of optimal cytoreduction is statistically lower in the Cases than Controls. At multivariate analysis, significant independent predictors for suboptimal residual disease resulted ED admission, peritoneal carcinosis and mesenteral involvement, supra radical surgery. CONCLUSIONS: Patients admitted from Emergency Department may have a lower likelihood of optimal cytoreduction, due to their poor clinical characteristics and large diffusion of the disease.

Integrated PET/CT as a first-line re-staging modality in patients with suspected recurrence of ovarian cancer.

PURPOSE: The aims of this study were to compare CT with PET/CT results in patients with suspected ovarian cancer recurrence and to assess the impact of the PET/CT findings on their clinical management. METHODS: Thirty-two consecutive patients with suspected ovarian cancer recurrence were retrospectively included in the study. Abdominal contrast-enhanced CT and PET/CT with [(18)F]FDG, in addition to conventional follow-up, were performed in all 32 patients. After the comparison between CT and PET/CT results, based on clinical reports, changes in the clinical management of patients (intermodality changes) due to PET/CT information were analysed. RESULTS: Twenty of the 32 patients were positive at CT (62.5%) versus 29 (90.6%) at PET/CT. Intermodality changes in management, i.e. use of a different treatment modality, after PET/CT examination were indicated in 14/32 (44%) patients. In particular, before PET/CT study, the planned management was as follows: wait-and-see in 7/32 (22%), further instrumental examinations in 4/32 (12%), chemotherapy in 10/32 (31%), diagnostic surgical treatment in 6/32 (19%) and surgical treatment in the remaining 5/32 (16%). After PET/CT study, wait-and-see was indicated in 1/32 (3%), further instrumental examinations in 7/32 (22%), chemotherapy in 16/32 (50%), diagnostic surgical treatment in 2/32 (6%) and surgical treatment in the remaining 6/32 (19%). CONCLUSION: Integrated PET/CT could detect tumour relapse in a higher percentage of patients than could CT. A change in the clinical management was observed in 44% of cases when PET/CT information was added to conventional follow-up findings.

Palliative care for intestinal obstruction in recurrent ovarian cancer: a multivariate analysis.

Bowel obstruction is the most common complication in patients with ovarian cancer. Management of this situation is controversial. The aim of our retrospective study was to determine the best approach for managing bowel obstruction in recurrent ovarian cancer. A retrospective analysis of data on 47 patients with intestinal obstruction by ovarian cancer was performed. Twenty-seven patients were submitted to surgery, with 21 intestinal procedures performed, 2 gastrostomy tubes placed, and 4 patients deemed inoperable. Twenty patients were managed medically with Octreotide (mean dosage of 0.48 mg/day), of which 1 patient required a nasogastric tube. Age, performance status, diagnosis of tumor to occlusion time, obstruction site, previous chemotherapy or radiotherapy, presence of ascites, or palpable masses were the variables analyzed. Student's t-test and Pearson chi-square test were used to compare the two different groups of treatment (surgical vs medical therapy). Disease-free-survival curves were plotted according to the Kaplan-Meier method and analyzed by the log-rank test. Cox's proportional hazards model was used for multivariate analysis. Values less than or equal to 0.05 were considered significant. The mean age of the patients was 58.7 years. Perioperative mortality and morbidity were both 22%. All patients died with minimal distress. Performance status results were significantly different between the patients submitted to surgery and patients treated with Octreotide (P= 0.03). No significant differences were found in the other variables analyzed. In multivariate analysis, only type of treatment emerges as a strong predictor of poor outcome (P < 0.001). Both surgery and Octreotide therapy are able to control distressing symptoms in end-stage ovarian cancer. Survival was significantly longer in the surgical group, and surgical palliation should be considered first in patients with good performance status.