Clinical utility of circulating tumor DNA sequencing with a large panel: a National Center for Precision Medicine (PRISM) study.

BACKGROUND: Circulating tumor DNA (ctDNA) sequencing is a promising approach for tailoring therapy in patients with cancer. We report hereby the results from a prospective study where we investigated the impact of comprehensive molecular profiling of ctDNA in patients with advanced solid tumors. PATIENTS AND METHODS: Genomic analysis was performed using the FoundationOne Liquid CDx Assay [324 genes, tumor mutational burden (TMB), microsatellite instability status]. Each individual genomic report was reviewed and discussed weekly by a multidisciplinary tumor board (MTB). Actionable targets were classified by ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) tier leading to molecular-based treatment suggestions wherever it was possible. RESULTS: Between December 2020 and November 2021, 1772 patients with metastatic solid tumors underwent molecular profiling. Median time to assay results was 12 days. Results were contributive for 1658 patients (94%). At least one actionable target was detected in 1059 patients (64%) with a total of 1825 actionable alterations including alteration of the DNA damage repair response pathway (n = 336, 18%), high TMB (>16 mutations/Mb; n = 243, 13%), PIK3CA mutations (n = 150, 8%), ERBB family pathway alterations (n = 127, 7%), PTEN alterations (n = 95, 5%), FGFR alterations (n = 67, 4%) and MET activations (n = 13, 0.7%). The MTB recommended a matched therapy for 597 patients (56%) with a total of 819 therapeutic orientations: clinical trials (n = 639, 78%), off-label/compassionate use (n = 81, 10%), approved drug (n = 51, 6%), and early access program (n = 48, 6%). In total, 122 patients (21%) were treated. Among the assessable patients (n = 107), 4 (4%) had complete response, 35 (33%) had partial response, 27 (25%) had stable disease, and 41 (38%) a progressive disease as best response. The median progression-free survival and median overall survival were 4.7 months (95% confidence interval 2.7-6.7 months) and 8.3 months (95% confidence interval 4.7-11.9 months) respectively. CONCLUSIONS: ctDNA sequencing with a large panel is an efficient approach to match patients with advanced cancer with targeted therapies.

Practical model to identify liver transplant recipients at low risk of postoperative haemorrhage, bile leakage and ascites.

BACKGROUND: This study aimed to identify a subgroup of recipients at low risk of haemorrhage, bile leakage and ascites following liver transplantation (LT). METHODS: Factors associated with significant postoperative ascites (more than 10 ml/kg on postoperative day 5), bile leakage and haemorrhage after LT were identified using three separate multivariable analyses in patients who had LT in 2010-2019. A model predicting the absence of all three outcomes was created and validated internally using bootstrap procedure. RESULTS: Overall, 944 recipients underwent LT. Rates of ascites, bile leakage and haemorrhage were 34.9, 7.7 and 6.0 per cent respectively. The 90-day mortality rate was 7.0 per cent. Partial liver graft (relative risk (RR) 1.31; P = 0.021), intraoperative ascites (more than 10 ml/kg suctioned after laparotomy) (RR 2.05; P = 0.001), malnutrition (RR 1.27; P = 0.006), portal vein thrombosis (RR 1.56; P = 0.024) and intraoperative blood loss greater than 1000 ml (RR 1.39; P = 0.003) were independently associated with postoperative ascites and/or bile leak and/or haemorrhage, and were introduced in the model. The model was well calibrated and predicted the absence of all three outcomes with an area under the curve of 0.76 (P = 0.001). Of the 944 patients, 218 (23.1 per cent) fulfilled the five criteria of the model, and 9.6 per cent experienced postoperative ascites (RR 0.22; P = 0.001), 1.8 per cent haemorrhage (RR 0.21; P = 0.033), 4.1 per cent bile leak (RR 0.54; P = 0.048), 40.4 per cent severe complications (RR 0.70; P = 0.001) and 1.4 per cent 90-day mortality (RR 0.13; P = 0.004). CONCLUSION: A practical model has been provided to identify patients at low risk of ascites, bile leakage and haemorrhage after LT; these patients could potentially qualify for inclusion in non-abdominal drainage protocols.

[Eruptive disseminated superficial porokeratosis associated with acute hepatitis E]. / Porokératose éruptive superficielle disséminée associée à une hépatite virale E aiguë.

BACKGROUND: Porokeratosis (PK) is a rare form of dermatosis characterized by a keratinization disorder of unknown etiology. Herein we describe the first case associated with hepatitis E virus infection. PATIENTS AND METHODS: A 69-year-old patient with colorectal cancer treated with radiation and chemotherapy followed by surgery in April 2017 presented two months later with jaundice associated with annular keratotic lesions of the skin with a raised border. Blood tests revealed elevated liver enzymes and hyperbilirubinemia. Viral hepatitis E was diagnosed based on serology and viral PCR after other aetiologies such as obstruction, auto-immune disease and other viruses (HAV, HBV, HCV, HSV, HIV, EBV and CMV) had been ruled out. A skin biopsy showed a cornoid lamella. Disseminated superficial porokeratosis associated with hepatitis E infection was then diagnosed. DISCUSSION: The mechanism of PK is unknown and probably involves a combination of different factors. PK has been described in patients with treatment-induced immunosuppression, solid cancer or AIDS, sometimes promoted by HCV viral infection, but never with concomitant HEV infection. A combination of immunosuppression induced by radio-chemotherapy and HEV infection could have prompted the development of PK in our patient. CONCLUSION: We report the first case of eruptive disseminated superficial porokeratosis associated with hepatitis E infection. The exact role of hepatitis E infection in the development of PK is still unclear.

Treatment of polycystic liver disease. Update on the management.

Polycystic liver disease (PLD) may consist of autosomal dominant PLD or isolated PLD without renal impairment. The natural history of liver cysts is to increase in size and number, causing progressive disease that can lead to very large and incapacitating hepatomegaly. Only symptomatic hepatomegaly (pain, inability to eat, weight loss, dyspnea) or cystic complications such as infection or intracystic hemorrhage should be treated. The treatment of PLD thus covers a wide range of therapeutic options, ranging from non-intervention to liver transplantation, including needle aspiration evacuation with injection of sclerosant, laparoscopic fenestration and fenestration by laparotomy combined with liver resection. The choice between these different treatments depends on the symptomatology, the intrahepatic extension of the lesions and the patient's general condition. Hepatic resection is commonly chosen since the vast majority of PLD consists of multiple small cysts that are impossible or difficult to fenestrate. Since cysts are inhomogeneously distributed in the hepatic parenchyma with most areas less affected, the preservation of this less-involved territory allows liver regeneration relatively free of cysts. Hepatectomies for PLD are technically difficult because the planes and the vascular and biliary structures are compressed by the cysts. Liver transplantation, whether isolated or associated with renal transplantation, is indicated in cases of severe malnutrition and/or end-stage renal disease or if the volume of remnant parenchyma is insufficient and suggests failure of a partial hepatectomy.

Efficacy and Safety of Everolimus and Mycophenolic Acid With Early Tacrolimus Withdrawal After Liver Transplantation: A Multicenter Randomized Trial.

SIMCER was a 6-mo, multicenter, open-label trial. Selected de novo liver transplant recipients were randomized (week 4) to everolimus with low-exposure tacrolimus discontinued by month 4 (n = 93) or to tacrolimus-based therapy (n = 95), both with basiliximab induction and enteric-coated mycophenolate sodium with or without steroids. The primary end point, change in estimated GFR (eGFR; MDRD formula) from randomization to week 24 after transplant, was superior with everolimus (mean eGFR change +1.1 vs. -13.3 mL/min per 1.73 m2 for everolimus vs. tacrolimus, respectively; difference 14.3 [95% confidence interval 7.3-21.3]; p < 0.001). Mean eGFR at week 24 was 95.8 versus 76.0 mL/min per 1.73 m2 for everolimus versus tacrolimus (p < 0.001). Treatment failure (treated biopsy-proven acute rejection [BPAR; rejection activity index score >3], graft loss, or death) from randomization to week 24 was similar (everolimus 10.0%, tacrolimus 4.3%; p = 0.134). BPAR was more frequent between randomization and month 6 with everolimus (10.0% vs. 2.2%; p = 0.026); the rate of treated BPAR was 8.9% versus 2.2% (p = 0.055). Sixteen everolimus-treated patients (17.8%) and three tacrolimus-treated patients (3.2%) discontinued the study drug because of adverse events. In conclusion, early introduction of everolimus at an adequate exposure level with gradual calcineurin inhibitor (CNI) withdrawal after liver transplantation, supported by induction therapy and mycophenolic acid, is associated with a significant renal benefit versus CNI-based immunosuppression but more frequent BPAR.

Liver Involvement in Patients With PiZZ-Emphysema, Candidates for Lung Transplantation.

Information about the prevalence and nature of liver disorders in adults with alpha1-antitrypsin deficiency is scarce. At our center, systematic liver biopsy screening is part of the evaluation before lung transplantation (LT) in the emphysema patients with the PiZZ phenotype. Our aim was to report our experience with this prospective screening. Clinical, liver function, and imaging parameters as well as liver histology data were analyzed for 23 consecutive adult patients with PiZZ severe emphysema referred to our center for consideration of LT from 2006 to 2014. Overall 20 (87%) featured chronic liver disease characterized by a chronic inflammation and/or a significant portal fibrosis on histology. Two of the 23 patients (8.7%) had septal fibrosis according to the Metavir and Ishak scores and met our definition of severe chronic liver disease. They were both clinically asymptomatic with normal liver function tests. On abdominal ultrasonography, the liver appeared normal in one patient and with abnormal contours in the other. Our data indicate that in adults with PiZZ-related emphysema being evaluated for LT, most patients had some histologic involvement. The prevalence of severe liver dysfunction is <10%.

Effect of camelina oil or live yeasts (Saccharomyces cerevisiae) on ruminal methane production, rumen fermentation, and milk fatty acid composition in lactating cows fed grass silage diets.

The potential of dietary supplements of 2 live yeast strains (Saccharomyces cerevisiae) or camelina oil to lower ruminal methane (CH4) and carbon dioxide (CO2) production and the associated effects on animal performance, rumen fermentation, rumen microbial populations, nutrient metabolism, and milk fatty acid (FA) composition of cows fed grass silage-based diets were examined. Four Finnish Ayrshire cows (53±7 d in milk) fitted with rumen cannula were used in a 4×4 Latin square with four 42-d periods. Cows received a basal total mixed ration (control treatment) with a 50:50 forage-to-concentrate ratio [on a dry matter (DM) basis] containing grass silage, the same basal total mixed ration supplemented with 1 of 2 live yeasts, A or B, administered directly in the rumen at 10(10) cfu/d (treatments A and B), or supplements of 60g of camelina oil/kg of diet DM that replaced concentrate ingredients in the basal total mixed ration (treatment CO). Relative to the control, treatments A and B had no effects on DM intake, rumen fermentation, ruminal gas production, or apparent total-tract nutrient digestibility. In contrast, treatment CO lowered DM intake and ruminal CH4 and CO2 production, responses associated with numerical nonsignificant decreases in total-tract organic matter digestibility, but no alterations in rumen fermentation characteristics or changes in the total numbers of rumen bacteria, methanogens, protozoa, and fungi. Compared with the control, treatment CO decreased the yields of milk, milk fat, lactose, and protein. Relative to treatment B, treatment CO improved nitrogen utilization due to a lower crude protein intake. Treatment A had no influence on milk FA composition, whereas treatment B increased cis-9 10:1 and decreased 11-cyclohexyl 11:0 and 24:0 concentrations. Treatment CO decreased milk fat 8:0 to 16:0 and total saturated FA, and increased 18:0, 18:1, 18:2, conjugated linoleic acid, 18:3n-3, and trans FA concentrations. Decreases in ruminal CH4 production to treatment CO were related, at least in part to lowered DM intake, whereas treatments had no effect on ruminal CH4 emission intensity (g/kg of digestible organic matter intake or milk yield). Results indicated that live yeasts A and B had no influence on animal performance, ruminal gas production, rumen fermentation, or nutrient utilization in cows fed grass silage-based diets. Dietary supplements of camelina oil decreased ruminal CH4 and CO2 production, but also lowered the yields of milk and milk constituents due to an adverse effect on intake.

Knockout of PARG110 confers resistance to cGMP-induced toxicity in mammalian photoreceptors.

Hereditary retinal degeneration (RD) relates to a heterogeneous group of blinding human diseases in which the light sensitive neurons of the retina, the photoreceptors, die. RD is currently untreatable and the underlying cellular mechanisms remain poorly understood. However, the activity of the enzyme poly-ADP-ribose polymerase-1 (PARP1) and excessive generation of poly-ADP-ribose (PAR) polymers in photoreceptor nuclei have been shown to be causally involved in RD. The activity of PARP1 is to a large extent governed by its functional antagonist, poly-ADP-glycohydrolase (PARG), which thus also may have a role in RD. To investigate this, we analyzed PARG expression in the retina of wild-type (wt) mice and in the rd1 mouse model for human RD, and detected increased PARG protein in a subset of degenerating rd1 photoreceptors. Knockout (KO) animals lacking the 110 kDa nuclear PARG isoform were furthermore analyzed, and their retinal morphology and function were indistinguishable from wild-type animals. Organotypic wt retinal explants can be experimentally treated to induce rd1-like photoreceptor death, but PARG110 KO retinal explants were unexpectedly highly resistant to such treatment. The resistance was associated with decreased PAR accumulation and low PARP activity, indicating that PARG110 may positively regulate PARP1, an event that therefore is absent in PARG110 KO tissue. Our study demonstrates a causal involvement of PARG110 in the process of photoreceptor degeneration. Contrasting its anticipated role as a functional antagonist, absence of PARG110 correlated with low PARP activity, suggesting that PARG110 and PARP1 act in a positive feedback loop, which is especially active under pathologic conditions. This in turn highlights both PARG110 and PARP1 as potential targets for neuroprotective treatments for RD.

[Current therapeutic approaches in inherited retinal degeneration: from genes to chip]. / Therapieansätze für erbliche Netzhauterkrankungen: von den Genen bis zum Chip.

Different strategies for the treatment of inherited photoreceptor degeneration are currently being investigated, with each of these approaches facing specific challenges. Gene therapy, for instance, may be feasible only for genetically well-defined pathologies. However, inherited retinal disorders are genetically highly heterogeneous and early onset disorders may restrict the therapeutic window. The majority of currently developed molecular approaches aim at the reconstitution of physiologically important functions in RPE and photoreceptor. Neuroprotection attempts to prolong cell survival and proper function via sustained delivery systems that fulfil a long-term dynamic reservoir function for therapeutic neuroprotective compounds. Cell-based approaches include replacement strategies such as cell transplantation, the implantation of prosthetic devices or optogenetics. They aim at replacing lost neurosensory functions of the retina. This short review aims at providing an insight into current therapeutic strategies and future treatment options for retinal disorders. Pharmacological and nutritional support strategies are only briefly discussed as we focus here on molecular and prosthetic therapeutic approaches.

Liver resection in transplanted patients: a single-center Western experience.

BACKGROUND: Liver resection (LR) in liver transplant (OLT) recipients, an extremely rare situation, who performed on 8 recipients. METHODS: This retrospective analysis of prospectively collected data concerned 8 (0.66%) 1198 LR cases among OLT performed from 1997 to 2011. We analyzed demographic data, surgical indications, and postoperative courses. RESULTS: The indications were resectable recurrent hepatocellular carcinomas (HCC, n = 3), persistent fistula from a posterior sectorial duct (n = 1), recurrent cholangitis due to anastomotic stricture on the posterior sectorial duct (n = l), hydatid cyst (n = l), left arterial hepatic thrombosis with secondary ischemic cholangitis (n = 1), and a large symptomatic biliary cyst (n = 1). The mean interval time to liver resection was 23.7 months (range, 5-47). LR included right hepatectomy (n = 1), right posterior hepatectomy (n = 1), left lobectomy (n = 4), pericystectomy (n = 1), or biliary fenestration (n = 1). Which there was no postoperative mortality, the global morbidity rate was 62% (5/8). The mean follow-up after LR was 92 months (range, 11-156). No patients required retransplantation. None of the 3 patients who underwent LR for HCC showed a recurrence. CONCLUSIONS: LR in OLT recipients is safe, but associated with a high morbidity rate. This procedure can avoid retransplantation in highly selected patients, presenting a possible option particularly for transplanted patients with a resectable, recurrent HCC.

Regression of new-onset diabetes mellitus after conversion from tacrolimus to cyclosporine in liver transplant patients: results of a pilot study.

INTRODUCTION: New-onset diabetes mellitus (NODM) has important implications for long-term outcome following liver transplantation. AIM: To evaluate the impact of conversion from tacrolimus to cyclosporine in liver transplant patients presenting NODM. METHOD: In a 12-month pilot study, 39 liver transplant patients with NODM were converted from tacrolimus to cyclosporine. Most patients (59%) were receiving antidiabetic therapy (18% insulin, 41% oral) and all patients had received dietary advice prior to the study. RESULTS: At month 12, NODM had significantly resolved (FBG<7 mmol/L without treatment) in 36% of patients (95% CI 20.8-51.0%). In the 16 patients not receiving antidiabetic drugs at baseline, mean FBG decreased from 8.1 mmol/L to 6.6 mmol/L (P=0.008) and mean HbA(1c) decreased from 6.4 to 6.0% (P=0.05). Steroids were stopped rapidly in the nine patients receiving steroids at inclusion but NODM resolution was observed in only one of these nine patients. No significant factors were identified that could have affected NODM resolution. There were three episodes of biopsy-proven acute rejection (7.7%), no graft losses and one death. Overall, cyclosporine tolerance was good with no significant change in creatinine clearance at month 12. Total cholesterol increased from 4.6 mmol/L to 5.1 mmol/L (P<0.001). CONCLUSIONS: These results suggest that liver transplant patients with NODM may benefit from conversion to cyclosporine from tacrolimus through improved glucose metabolism. Confirmation in a prospective, randomized comparative study is required.

[Comparison between Lenstar LS 900 non-contact biometry and OcuScan RXP contact biometry for task delegation]. / Comparaison de la biométrie sans contact cornéen par LENSTAR LS 900 et de la biométrie contact par OCUSCAN RXP dans le cadre de la délégation de tâches.

INTRODUCTION: Non-contact biometers have many advantages including the delegation of tasks to orthoptists. This study analyses the reliability of measurements comparing contact and non-contacts techniques. PATIENTS AND METHODS: Comparative measurements were taken on 86 eyes of 45 patients (mean age: 74 years; 44.4 % males) in preoperative phacoemulsification by three orthoptists with experience in this task. Each patient had non-contact measurements (Lenstar LS 900, Haag-Streit) and contact measurements (corneal biometry and ultrasound pachymetry with OcuScan RXP, Alcon) and a keratometry refractometer (TONOREF II, Nidek). The axial length data, pachymetry, power of the intraocular lens (SRK/T formula), anterior chamber depth, and the average keratometry were analyzed by paired comparisons. RESULTS: The non-contact biometer was ineffective in 5.8 % of cases (Parkinson's disease, two cases; dense posterior subcapsular cataracts, three cases). The non-contact pachymetry was statistically significantly higher (546.4 µm vs. 538.6 µm; p<0.001). The axial length was significantly longer for the non-contact measurement (23.21 mm vs. 23.05 mm; p<0.0001). In 25.9 % of patients, this difference was greater than or equal to 0.3mm and affected the power of the implant chosen. The anterior chamber depth measured on non-contact biometry was statistically greater (3.33 mm vs. 3.03 mm; p<0.0001). However, there was no significant difference regarding the average keratometry (43.82 D vs. 43.78 D; p=0327). CONCLUSION: Besides the infectious benefit for patients, absence of cleaning and decontamination of biometric probes, non-contact measurements using Lenstar are an example of a safe activity that can be delegated to assistants. This technique has been used to optimize the refractive outcome of 25.9 % of our patients undergoing refractive cataract surgery.

DSM-based problem gambling: increasing the odds of heavy drinking in a national sample of U.S. college athletes?

Despite previously found co-occurrence of youth gambling and alcohol use, their relationship has not been systematically explored in a national sample using DSM-based gambling measures and multivariate modeling, adjusted for potential confounders. This study aimed to empirically examine the prevalence patterns and odds of at-least-weekly alcohol use and heavy episodic drinking (HED) in relation to various levels of gambling severity in college athletes. Multivariate logistic regression analyses were performed on data from a national sample of 20,739 U.S. college athletes from the first National Collegiate Athletic Association national survey of gambling and health-risk behaviors. Prevalence of at-least-weekly alcohol use significantly increased as DSM-IV-based gambling severity increased, from non-gambling (24.5%) to non-problem gambling (43.7%) to sub-clinical gambling (58.5%) to problem gambling (67.6%). Multivariate results indicated that all levels of gambling were associated with significantly elevated risk of at-least-weekly HED, from non-problem (OR = 1.25) to sub-clinical (OR = 1.75) to problem gambling (OR = 3.22); the steep increase in the relative risk also suggested a possible quadratic relationship between gambling level and HED risk. Notably, adjusted odds ratios showed problem gambling had the strongest association with at-least-weekly HED, followed by marijuana (OR = 3.08) and cigarette use (OR = 2.64). Gender interactions and differences were also identified and assessed. In conclusion, attention should be paid to college athletes exhibiting gambling problems, especially considering their empirical multivariate associations with high-risk drinking; accordingly, screening for problem gambling is recommended. More research is warranted to elucidate the etiologic mechanisms of these associations.

The risk of surgery in patients with cirrhosis.

Several reasons result in the finding that patients with cirrhosis need surgery more often than other patients groups. Patients with cirrhosis frequently have comorbidities resulting in gastrointestinal, lung or cervical cancer, among others. Independent of cirrhosis, surgical resection may be the best alternative for a number of those malignancies. Comorbidities may also result in an increased incidence of vascular complications (such as lower extremity atherosclerosis and coronary stenosis) some of them being potential indications for surgery. Patients with alcoholic cirrhosis are more frequently subjected to trauma and bone fractures. Ascites leads to umbilical hernia which can be strangulated or ruptured. Emergency surgery may be needed in this context. Finally, a significant proportion of patients with cirrhosis develop hepatocellular carcinoma (HCC) during the course of the disease. Surgical resection remains a first line option for HCC. While reliable guidelines have been proposed for surgical resection of HCC and liver transplantation, no precise guidelines are available for other aspects of surgical management during cirrhosis. Specific surgical procedures such as hepatectomy and transplantation are concentrated in highly specialised centres, where detailed evaluation is relatively easy to obtain. In contrast, more general surgical procedures, either abdominal or non abdominal, are performed in various centres, making it more difficult to obtain detailed evaluation and draw recommendations. General surveys are still needed to precisely assess the risk of non-specific surgery in patients with cirrhosis, to identify risk factors and to propose reliable guidelines.

Hepatocellular carcinoma in Budd-Chiari syndrome: characteristics and risk factors.

BACKGROUND AND AIMS: To analyse the characteristics of and the factors associated with the development of hepatocellular carcinoma (HCC) in patients with Budd-Chiari syndrome (BCS). PATIENTS AND METHODS: 97 consecutive patients with BCS and a follow-up > or = 1 year were evaluated retrospectively. Liver nodules were evaluated using serum alpha-fetoprotein (AFP) level and imaging features (CT/MRI). Biopsy of nodules was obtained when one of the following criteria was met: number < or = 3, diameter > or = 3 cm, heterogeneity, washout on portal venous phase, increase in size on surveillance, or increase in AFP level. RESULTS: Patients were mainly Caucasian (69%) and female (66%). Mean age at the diagnosis of BCS was 35.8 (SE 1.2 years), and median follow-up 5 years (1-20 years). The inferior vena cava (IVC) was obstructed in 13 patients. Liver nodules were found in 43 patients, 11 of whom had HCC. Cumulative incidence of HCC during follow-up was 4%. Liver parenchyma adjacent to HCC showed cirrhosis in nine patients. HCC was associated with male sex (72.7% v 29.0%, p = 0.007); factor V Leiden (54.5% v 17.5%, p = 0.01); and IVC obstruction (81.8% v 4.6%, p < 0.001). Increased levels of serum AFP were highly accurate in distinguishing HCC from benign nodules: PPV = 100% and NPV = 91% for a cut-off level of 15 ng/ml. CONCLUSION: The incidence of HCC in this large cohort of BCS patients was similar to that reported for other chronic liver diseases. IVC obstruction was a major predictor for HCC development. Serum AFP appears to have a higher utility for HCC screening in patients with BCS than with other liver diseases.

Ultraviolet A1 phototherapy for treatment of acrosclerosis in systemic sclerosis: controlled study with half-side comparison analysis.

BACKGROUND: Treatments currently used in acrosclerosis for patients with systemic sclerosis (SS) are not very efficient and are associated with adverse effects. Several reports concern the efficacy of ultraviolet A1 (UVA1) phototherapy for localized scleroderma. Recent studies appear to indicate the interest of UVA1 in acrosclerosis for patients with SS. However, these studies are uncontrolled. OBJECTIVE: To determine whether UVA1 phototherapy is effective for acrosclerosis in SS with a randomized, investigator-blinded, controlled study. METHODS: Nine patients with SS completed the study. The duration of disease ranged from 6 to 21 years. None of them had received glucocorticoids or immunosuppressive agents. Low-dose UVA1 phototherapy (40 J/cm(2)) of the randomized hand was performed three times weekly over a period of 14 weeks. The other hand served as control. The clinical evaluation used a modified semiquantitative skin scoring system, the index flexion and extension, and a visual analog scale (VAS) was performed at baseline and after treatment. RESULTS: The mean of skin score and VAS improved significantly (P<0.05), but this improvement does not appear to be different between the treated or the untreated hands. There was no modification of the index flexion or extension. Two patients noticeably improved the functions of the treated hand. No side effects were observed. CONCLUSIONS: These results suggest that UVA1 phototherapy does not improve cutaneous thickness in acrosclerosis even if few functional improvements, and some ulcerations healings can be occasionally observed. However, a larger scale trial is necessary to confirm this inefficiency.

Chemoimmunotherapy with low dose vinorelbine and interleukin-2 in treatment of patients with metastatic renal cell carcinoma.

Systemic therapies employed in patients with metastatic renal cell carcinoma (MRCC) include chemotherapy to immunomodulatory cytokines (interleukin 2 [IL-2], interferon alpha [INFalpha]), chemoimmunotherapy, adoptive immune therapy and anti-angiogenic therapy. Despite this range of treatment alternatives, the optimal therapy for MRCC patients is far from being established. Thus, attempts with novel therapeutic approaches implementing new drug combinations are justified. We conducted a phase II evaluation of a combination of vinorelbine and IL-2, both at low doses, in 30 patients with MRCC. The rationale of the combination was to damage the tumor tissue to the extent necessary to make it more immunogenic while, at the same time, to obtain an efficient immune response through the concomitant administration of IL-2. The treatment, given in different dose combinations and administration times, resulted feasible, with no renal, neurological or hematological toxicity. The overall survival of the whole group of patients is higher than that usually observed following treatment with immunotherapies (18.2 versus 13.3 months, respectively). While the limited number of treated patients does not allow advancing conclusions on the effective activity of the adopted protocol, the results observed are encouraging.