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Disease-specific autoantibodies are considered the most important biomarkers for systemic sclerosis (SSc), due to their ability to stratify patients with different severity and prognosis. Anti-nuclear antibodies (ANA), occurring in subjects with isolated Raynuad’s phenomenon, are considered the strongest independent predictors of definite SSc and digital microvascular damage, as observed by nailfold videocapillaroscopy. ANA are present in more than 90% of SSc, but ANA negativity does not exclude SSc diagnosis: a little rate of SSc ANA negative exists and shows a distinct subtype of disease, with less vasculopathy, but more frequent lower gastrointestinal involvement and severe disease course. Anti-centromere, anti-Th/To, and anti-Topoisomerase I antibodies could be considered as classical biomarkers, covering about 60% of SSc and defining patients with well-described cardio-pulmonary complications. In particular, anti-Topoisomerase I represent a risk factor for development of diffuse cutaneous involvement and digital ulcers in the first 3 years of disease, as well as severe interstitial lung disease (ILD). Anti-RNA polymerase III is a biomarker with new clinical implications: very rapid skin thickness progression, gastric antral vascular ectasia, the occurrence of synchronous cancers, and possible association with silicone breast implants rupture. Moreover, novel SSc specific autoantibodies have been globally described in about 10% of “seronegative” SSc patients: anti-elF2B, anti-RuvBL1/2 complex, anti-U11/U12 RNP, and anti-BICD2 depict specific SSc subtypes with severe organ complications. Many autoantibodies could be considered markers of overlap syndromes, including SSc. Anti-Ku are found in 2–7% of SSc, strictly defining the PM/SSc overlap. They are associated with synovitis, joint contractures, myositis, and negatively associated with vascular manifestation of disease. Anti-U3RNP are associated with a well-defined clinical phenotype: Afro-Caribbean male patients, younger at diagnosis, and higher risk of pulmonary hypertension and gastrointestinal involvement. Anti-PM/Scl define SSc patients with high frequency of ILD, calcinosis, dermatomyositis skin changes, and severe myositis. The accurate detection of autoantibodies SSc specific and associated with overlap syndromes is crucial for patients’ stratification. ANA should be correctly identified using indirect immunofluorescent assay and a standardized way of patterns’ interpretation. The gold-standard technique for autoantibodies’ identification in SSc is still considered immunoprecipitation, for its high sensitivity and specificity, but other assays have been widely used in routine practice. The identification of SSc autoantibodies with high diagnostic specificity and high predictive value is mandatory for early diagnosis, a specific follow-up and the possible definition of the best therapy for every SSc subsets. In addition, the validation of novel autoantibodies is mandatory in wider cohorts in order to restrict the gap of so-called seronegative SSc patients.

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a new intraabdominal technique to approach non-resectable peritoneal carcinomatosis (PC). PIPAC can be performed alone or alternated with systemic chemotherapy to increase tumor regression. We describe our initial experience performed in an expert hyperthermic intraperitoneal chemotherapy (HIPEC) French center to demonstrate the safety and the feasibility of PIPAC. Between January 2016 and March 2019, PIPAC was proposed to 43 consecutive patients affected by digestive, ovarian, peritoneal and mammary carcinomatosis. Initially PIPAC was proposed to patients non eligible for cytoreductive surgery for palliative purposes. In five patients we associated PIPAC to systemic chemotherapy to improve tumor regression and enhance the chance of patients to undergo HIPEC. Three PIPAC treatments were supposed to be performed for each patient with an interval of 6 weeks in between each procedure. Peritoneal biopsies were always performed to evaluate microscopic tumor regression. In case of postoperative clinical deterioration or quick tumor progression during the cycles, PIPAC was interrupted. Depending on the primary tumor, chemotherapies used were oxaliplatin or a combination of cisplatin and doxorubicin. Twenty-six (60.4%) patients have already had a surgical resection or intervention of primary cancer removal. In 5 patients abdominal access was impossible. Of the 38 patients operated, seventy-one procedures were performed. In the series, one patient died because of tumor progression. Only one major complication occurred intraoperatively. Two of thirteen patients receiving oxaliplatin had postoperative abdominal pain and needed more drugs assumption and a longer hospitalization. Three patients after a three cycles procedure underwent HIPEC. Nine of the patients who had at least two PIPACs had last biopsies showing a major or complete tumor response. PIPAC is a safe and feasible procedure that can be performed in patients with peritoneal carcinomatosis initially not eligible for surgery to reduce tumor invasion or for palliation to reduce symptoms. Contraindications are bowel obstruction and multiple intraabdominal adhesions.

Purpose of Review To highlight the recent discoveries and lines of evidence on the role of microRNAs in ankylosing spondylitis (AS) and psoriatic arthritis (PsA), focusing on their expression profiling and mechanisms of action. Recent Findings AS and PsA are chronic inflammatory musculoskeletal diseases with axial manifestations and represent an excellent model for studying microRNAs contribution to the disease pathogenesis, particularly through immunomodulation, inflammation, and bone remodelling, or their value as candidate diagnostic and prognostic biomarkers. Summary MicroRNAs are single-stranded nucleotides able to regulate gene expression. They are a key component of the epigenetic machinery, involved in physiological and pathological processes. The contribution of microRNAs in AS and PsA (such as miR-29a in regulating bone metabolism) is highlighted by several works in the field but their utility as possible markers must be still confirmed, particularly in larger patients’ cohorts.

This research focused on the effect of storage time on the chemical composition of the pyroligneous liquor (PL) produced during the pyrolysis of eucalyptus wood in a laboratory furnace at a relatively low heating rate (1 °C min−1) and a maximum temperature of 400 °C. The chemical compounds present in PL were identified through gas chromatography-mass spectrometry. This analysis was repeated over 19 months to observe changes in PL composition. Compounds such as 1,2-butanediol, 2-methoxytetrahydrofuran, 1,2-cyclopentanedione were only detected in the fresh PL and not after 11 or 19 months of storage. On the other hand, in PL stored for 11 and 19 months, new compounds were found, such as propanoic acid, butanediol, 5,9-dodecadien-2-one,6-10-dimethyl cyclopentanone, which were not observed in fresh PL. This suggests that PL from eucalyptus wood pyrolysis contains reactive compounds, mainly oxygenated, that interact during storage. Regarding the moment of stabilization of the qualitative composition of the PL, this research suggests that it is only reached after 11 months of storage. Phenol and furan derivatives were found to be stable, only reacting in their side chains without affecting the central ring. On the other hand, derivatives of tetrahydrofuran showed significant reactivity and tended to disappear with storage time.

The pyroligneous extract is an organic substance resulting of condensation of the smoke generated by the carbonization of the wood. It has at least 80% of water and contains several compounds. It is hypothesized that some of these compounds could have preservative properties for cosmetic and sanitizing products. This study evaluates the characteristics and antifungal properties of the pyroligneous extracts from eucalyptus wood, obtained from (i) laboratorial and (ii) commercial production. The possibility of using the pyroligneous extract as a preservative is also assessed, comparing it with formaldehyde. The chemical compounds of both extracts were identified by a gas chromatograph connected to a mass spectrometer (GC/MS). In general, oxygenated gamma components, such as carboxylic acids, esters, ethers, and ketenes, were identified. Phenol, guaiacol, and phenol derivatives were also detected. The best antifungal results were obtained with laboratorial pyroligneous extract. The potential actives under consideration from the samples were: corilon, mequinol, 2-metoxy 4-methylphenol, 4-ethyl 2-methoxyphenol, 2,6-dimetoxyphenol,1,2,4-trimetoxybenzene, and 5-tert-butylpyrogallol. Toxic compounds were found in both studied extracts, which restrict use in cosmetic products, as they require previous removals, although they are still promising in sanitising products.

Autoantibodies specific for idiopathic inflammatory myopathy (myositis-specific autoantibodies (MSAs)) are clinically useful biomarkers to help the diagnosis of polymyositis/dermatomyositis (PM/DM). Many of these are also associated with a unique clinical subset of PM/DM, making them useful in predicting and monitoring certain clinical manifestations. Classic MSAs known for over 30 years include antibodies to Jo-1 (histidyl transfer RNA (tRNA) synthetase) and other aminoacyl tRNA synthetases (ARS), anti-Mi-2, and anti-signal recognition particle (SRP). Anti-Jo-1 is the first autoantibodies to ARS detected in 15-25 % of patients. In addition to anti-Jo-1, antibodies to seven other aminoacyl tRNA synthetases (ARS) have been reported with prevalence, usually 1-5 % or lower. Patients with any anti-ARS antibodies are associated with anti-synthetase syndrome characterized by myositis, interstitial lung disease (ILD), arthritis, Raynaud's phenomenon, and others. Several recent studies suggested heterogeneity in clinical features among different anti-ARS antibody-positive patients and anti-ARS may also be found in idiopathic ILD without myositis. Anti-Mi-2 is a classic marker for DM and associated with good response to steroid treatment and good prognosis. Anti-SRP is specific for PM and associated with treatment-resistant myopathy histologically characterized as necrotizing myopathy. In addition to classic MSAs, several new autoantibodies with strong clinical significance have been described in DM. Antibodies to transcription intermediary factor 1γ/α (TIF1γ/α, p155/140) are frequently found in DM associated with malignancy while anti-melanoma differentiation-associated gene 5 (MDA5; CADM140) are associated with clinically amyopathic DM (CADM) complicated by rapidly progressive ILD. Also, anti-MJ/nuclear matrix protein 2 (NXP-2) and anti-small ubiquitin-like modifier-1 (SUMO-1) activating enzyme (SAE) are recognized as new DM-specific autoantibodies. Addition of these new antibodies to clinical practice in the future will help in making earlier and more accurate diagnoses and better management for patients.

Thymic epithelial tumors (TETs) are rare tumors of the mediastinum, with an estimated incidence of about 3 cases per 100,000 inhabitants. Although anthracycline- and platinum-based chemotherapy is an active treatment for TETs, novel systemic therapeutic options are especially needed for metastatic disease, which is virtually incurable. On the basis of the radiographic response obtained with imatinib (Novartis Pharma, Basel, Switzerland) in a patient with thymic carcinoma harboring the V560del c-KIT mutation, a phase II trial was initiated at the Department of Molecular and Clinical Oncology and Endocrinology of University “Federico II of Naples” with the purpose to test imatinib in TETs. Imatinib was daily delivered at the dose of 400 mg to patients affected by TETs, who had progressed after at least one chemotherapy regimen. Positivity of c-KIT on immunohistochemistry was not mandatory for study entry. Radiographic responses were measured by CT scans performed every 3 months, according to the RECIST criteria. Toxicity was graded according to the Common Toxicity Criteria of the National Cancer Institute, version 3.0. Fifteen patients with advanced TETs were enrolled from March 2008 to May 2010. Three patients presented with thymic carcinomas. Two of these three patients presented c-kit expression on immunohistochemistry. No patient harbored a known c-kit activating mutation. Imatinib was very well tolerated, with no toxicity-related death. Diarrhea and migraine were the most frequent events, occurring both in 20% of patients, but were manageable and mild. No radiographic responses were recorded. Median progression-free survival was 3 months (interquartile range, 2.5–4). Median overall survival was not reached. The study was terminated before it reached its target accrual of 42 patients, because of the lack of responses and low accrual rate. This trial indicates the lack of effectiveness of imatinib in unselected patients with thymic epithelial tumors. Nevertheless, imatinib may represent a valuable option in selected patients with TETs, such as those harboring the V560del c-KIT mutation.

Many tumor cells express chemokines and chemokine receptors, and these molecules can affect both tumor progression and anti-tumor immune response. Genetic polymorphisms of some chemokine receptors were found to be closely related to malignant tumors, especially in metastasis process, including breast cancer (BC). Considering this, it was investigated a possible role for CCR2-V64I (C-C chemokine receptor 2) and CCR5-Δ32 (C-C chemokine receptor 5) genetic variants in BC context. Patients were divided into subgroups according to immunohistochemical profile of estrogen (ER) and progesterone (PR) receptors and the human epidermal growth factor receptor 2 (HER2) overexpression. No significant associations were found in relation to susceptibility (CCR2-V64I: OR 1.32; 95 % CI 0.57-3.06; CCR5-∆32: OR 1.04; 95 % CI 0.60-1.81), clinical outcome (tumor size, lymph nodes commitment and/or distant metastasis, TNM staging and nuclear grade) or therapeutic response (recurrence and survival). However, it was found a significant correlation between CCR2-V64I allelic variant and HER2 immunohistochemical positive samples (p = 0.026). All in all, we demonstrate, for the first time, a positive correlation between CCR2 receptor gene polymorphism and a subgroup of BC related to poor prognosis, which deserves further investigation in larger samples for validation.

Robotic surgery was introduced as a means of overcoming the limitations of traditional laparoscopy. This report describes the results of a matched comparative study between traditional (TLLR) and robot-assisted laparoscopic liver resection (RLLR) performed in two European centers. From January 2008–April 2013, 46 patients underwent RLLR at San Matteo degli Infermi Hospital. Each patient was matched to a patient who had undergone TLLR at Antoine Beclere Hospital. The variables evaluated were operative time, blood loss, conversion rate, morbidity, mortality, and length of hospital stay. Twenty-eight patients were included in each group. Despite matching, more tumors were solitary in the TLLR group (P = 0.02) and more were localized in the superior and posterior segments in the RLLR group (P = 0.003). The median duration of surgery was 210 and 176 min in the RLLR and TLLR groups, respectively (P = 0.12). Conversion rate, blood loss, morbidity, and length of stay were similar in both groups. In multivariate analysis in all cohorts of patients, the sole independent risk factor of postoperative complications was the operative duration [OR = 1.016; P = 0.007]. Robotic LLR is associated with outcomes similar to those obtained with TLLR. However, robotics may facilitate LLR in patients with superior and posterior liver tumors.

Anemia is one of the most common hematological manifestations in SLE patients, occurring in about 50% of active cases. STAT1 is a critical signaling molecule required for the production of type-1 interferon (I-IFN), CCL2, and CXCL10, all of which are upregulated in SLE. Overexpression of STAT1 has been described to be involved in anemia in animal models. The aim of this study is to analyze how these components are involved in SLE-associated anemia.Blood samples were collected from 39 healthy donors and 101 SLE patients fulfilling ACR criteria. Samples were collected from a total of 180 visits (58 patients had 2 or more visits) of which 52 visits included a diagnosis of anemia. Healthy donors had only single visit. Total RNA, isolated from leukocytes, was analyzed by Taqman qPCR. Relative expression levels of I-IFN signature genes, chemokines, and miR-146a were determined by the ΔΔCT method. Results were correlated with clinical data and analyzed by the Wilcoxon/Kruskal-Wallis test and Fisher's exact test.Significant increases in IFN score (p0.0001), STAT1 (p0.0001), miR-146a (p0.0005), CCL2 (p = 0.0047), and CXCL10 (p = 0.017), as well as a significant decrease in pri-miR-146a (p = 0.0002), were detected in the anemic SLE patient visits (n = 52) compared to non-anemic SLE visits (n = 128). Regardless of disease activity, lupus nephritis, or race, anemic SLE patients displayed significantly elevated levels of STAT1 and miR-146a compared to non-anemic SLE patients.STAT1 and miR-146a may be upregulated during inflammation and via proinflammatory cytokines and chemokines in SLE. Prolonged upregulation of STAT1 and miR-146a appears to play an important role in anemia in SLE patients.

In the past decade, our knowledge of the mechanisms producing disease during acute and chronic infections with hepatitis B (HBV) and C (HCV) viruses has solidified the fact that the immune response induced by these viruses plays dominant roles. It is becoming increasingly clear that HBV and HCV can subvert the host immune system to survive, and the viral persistence can also induce autoimmune manifestations that complicate the clinical setting and may contraindicate therapies that indiscriminately augment immune effector mechanisms [1]. The liver is considered as an “immunological organ”, with innate immune functions and cells [2] that aid in the recognition of HBV and HCV antigens, leading to the production of type I interferons (I-IFN) and inflammatory cytokines that inhibit the viral replication [3]. This is potentially beneficial in clearing viral infections, but may also initiate liver fibrosis, increasing the risk of cirrhosis and the subsequent risk of hepatocellular carcinoma (HCC) [4]. In the case of HBV, chronic liver disease afflicts approximately 300– 400 million people worldwide, despite the availability of a safe and effective vaccine [5]. HCV infects up to 170 million persons worldwide and the development of cirrhosis is associated with an annual incidence of HCC of 3–5 % [6, 7]. Currently, HCV infection, resulting in cirrhosis and/or HCC, is the leading indication for orthotopic liver transplantation in developed countries [6, 7]. To provide a comprehensive view of the newest information regarding HBV and HCV infections, the articles presented in this special issue of Seminars in Immunopathology focus on the most controversial immunopathological aspects associated with both infections. These articles provide new evidence of the link between the immune response and virus survival within hepatocytes, elucidate occult infections and the risk of recurrent hepatitis in liver transplanted patients, and describe the autoimmunity associated with chronic HBV and HCV infections. The contributions to this special issue prove a deeper understanding of the mechanisms by which hepatitis and its complications are caused by the viruses themselves as well as by inflammation and immunological mechanisms that culminate in chronic liver damage. For pragmatic purposes, we have arbitrarily subdivided the themes discussed in this issue between suspected and unsuspected factors involved in the pathogenesis (Table 1). One limitation in the study of HBVand HCV infections is the lack of understanding in the replication strategies used by these viruses to persist in infected liver cells. Dandri et al. describe the most recent experimental models developed for the study of HBV, that are surrogates because HBV infection occurs naturally only in human beings and chimpanzee, which limits potential studies due to obvious practical and ethical problems. These numerous in vitro systems and animal models (i.e. murine, duck, woodchuck and tree shrew) have provided a better insight into the progress of HBV infection, and have been helpful in understanding the immunopathogenesis and testing of new therapeutic strategies. It is important to highlight the role of the innate immune system in response to viral hepatitis, and in fact This article is a contribution to the special issue on Immunopathology of Viral Hepatitis _ Guest Editors: C. Selmi and J. M. Vierling C. Selmi :A. Ceribelli Rheumatology and Clinical Immunology, Humanitas Clinical and Research Center, Milan, Italy

While inflow occlusion techniques are accepted methods to reduce bleeding during open liver surgery, their use in laparoscopic liver resections are limited by possible effects of pneumoperitoneum on ischemia-reperfusion liver damage. This retrospective study was designed to investigate the impact of intermittent pedicle clamping (IPC) on patients with normal liver undergoing minor laparoscopic liver resections. Three matched groups of patients were retrospectively selected from our in-house database: 11 patients who underwent robot-assisted liver resection with IPC, and 16 and 11 patients who underwent robot-assisted liver resection without IPC and open liver resection with IPC, respectively. The primary end point was to assess differences in postoperative serum alanine, aspartate aminotransferase (ALT and AST) and bilirubin levels. The curves of serum AST, ALT and bilirubin levels in a span of time of five postoperative days were not significantly different between the three groups. IPC has no relevant effects on ischemia-reperfusion liver damage even in the presence of pneumoperitoneum.

The aim of the study is to describe techniques of robot-assisted parenchymal-sparing liver surgery.Laparoscopy provides the same oncologic outcomes as open liver resection and better early outcome. Limitations of laparoscopy remain resections in posterior and superior liver segments, frequently approached with laparoscopic right hepatectomy, bleeding from the section line, and prolonged operative times when a combined procedure is needed.We retrospectively analyzed our series of robot-assisted liver resections between 2008 and September 2010 to evaluate whether robot assistance can overcome the limitations of laparoscopy.A total of 23 patients underwent robot-assisted liver resection for a total of 21 subsegmentectomies, 6 segmentectomies, 2 segmentectomies S6 + subsegmentectomies S7, 1 bisegmentectomy S2-3, and 2 pericystectomies. In ten cases (47.8%) liver nodules were located in the posterior and superior liver segments. In three cases the tumor was in contact with a main portal branch and in two cases with a hepatic vein. In one case the tumor had contact with both hepatic vein and portal branch. In the latter cases a no-margin resection was carried out. In 16 cases (65.5%) liver resection was associated with a concomitant procedure (10 laparoscopic colectomies, 1 robotic rectal resection, 3 laparoscopic radiofrequency ablations, and 2 extensive adhesiolyses). Mean operative time was 280 ± 101 min, blood loss was 245 ± 254 ml, and mean hospital stay was 8.9 ± 9.4 days. Mortality was nil. One case of biliary leakage and two of intraoperative hemorrhage requiring transfusion were the main complications encountered.Robot assistance allows optimal access to all liver segments and facilitates parenchymal-sparing surgery also for lesions located in the posterosuperior segments or in contact with main liver vessels.

Autoantibodies to topoisomerase I (topo I), RNA polymerase III (RNAPIII), centromere, U3RNP/fibrillarin, Th, PM-Scl, and U1RNP found in scleroderma (SSc) are associated with unique clinical subsets. The effects of race and gender on autoantibody prevalence and clinical manifestations were examined. Autoantibodies in sera from 105 SSc (include 75 Caucasian, 24 African-American, 6 others; 89 females and 16 males) were analyzed by immunofluorescence and immunoprecipitation. Clinical information was from database. SSc-related autoantibodies seldom coexist except for anti-topo I and anti-U1RNP. Anti-topo I (35% vs 15%), anti-U3RNP (30% vs 3%, p = 0.0005), and anti-U1RNP (30% vs 13%) were more common in African-Americans vs Caucasians. Anti-centromere (17%) and anti-PM-Scl (only in 8% of female) were found only in Caucasians. In race/gender combination, all three African-American males had anti-topo I (p = 0.04). Anti-U3RNP (35% vs 3%, p = 0.0005) and anti-U1RNP were common in African-American females. In African-American, all nucleolar dominant staining sera had anti-U3RNP; nuclear pattern was topo I (50%), U1RNP (19%), and RNAPIII (13%). In Caucasian, nucleolar was anti-Th (43%) and PM-Scl (29%); nuclear pattern was RNAPIII (29%), topo I (24%), and U1RNP (18%). Anti-topo I, anti-RNAPIII, and anti-U3RNP were associated with diffuse SSc while anti-centromere, anti-Th, and anti-U1 with limited disease. Proximal scleroderma was less common in African-American with anti-topo I (38% vs 91% in Caucasian, p = 0.04). The production of SSc-related autoantibodies is gender and race dependent, and this can be highly relevant in understanding their clinical significance.

Purpose Nailfold videocapillaroscopy (NVC) identifies the microvascular hallmarks of systemic sclerosis (SSc) and vascular endothelial growth factor (VEGF) and may play a pivotal role in the associated vasculopathy. The aim of the present study was to compare NVC alterations with clinical subsets, internal organ involvement, and serum VEGF levels in a cohort of selected SSc cases. Methods We studied 44 patients with SSc who were evaluated within 3 months from enrollment by NVC, skin score, severity index, pulmonary function tests, carbon monoxide diffusing capacity (DLCO), echocardiography, pulmonary high-resolution computed tomography (HRCT), gastroesophageal (GE) endoscopy or manometry or X-ray, and serum autoantibodies. Serum VEGF-A levels were determined by ELISA in 72 SSc patients and 31 healthy controls. Results Giant capillaries were inversely correlated with age (p = 0.034, r = −0.34) and to the extent of reticular pattern at HRCT (p = 0.04, r = −0.5). Avascular areas were directly correlated with capillaroscopy skin ulcer risk index (CSURI) (p = 0.006, r = +0.4) and severity index (p = 0.004, r = +0.5). The mean capillary density was directly correlated to the ulcer number (p = 0.02, r = +0.4) and to DLCO/alveolar volume (p = 0.02, r = +0.4) and inversely correlated with severity index (p = 0.01, r = −0.4) and skin score (p = 0.02, r = −0.4). Serum VEGF levels were higher in the SSc population vs controls (p = 0.03) and inversely correlated with DLCO (p = 0.01, r =−0.4) and directly with ground-glass and reticular pattern at HRCT (p = 0.04, r = +0.4 for both). Conclusions Our data suggest the importance of NVC not only for the diagnosis, but also for the global evaluation of SSc patients. Of note, serum VEGF levels may act as a biomarker of interstitial lung involvement.

Purpose: Patients with advanced non-small-cell lung cancer (NSCLC) have a short life expectancy; therefore, in addition to increasing their survival, improving their quality of life (QoL) is also an important treatment goal. Methods: We evaluated the QoL of patients with advanced NSCLC who were unfit to receive chemotherapy, failed to respond or progress following prior chemotherapy, who received subsequent treatment with gefitinib (‘Iressa’) on a compassionate use basis, using a standard QoL questionnaire, (EORTC) QLQ-C30 and the related lung cancer-specific module QLQ-LC13. Results: Analysis of the functional scales showed a trend towards improvement for role, emotional and cognitive scales, while a substantial stability was seen for general QoL scale. Analysis of the symptoms scales of QLQ-C30, showed a trend towards improvement for fatigue, dyspnoea, insomnia, and constipation, after one month of therapy. Fifty-six of the 57 patients were considered evaluable for response. One patient evidenced a partial response (patient is still on response), 29 patients had stable disease for a median duration of 5months (range 4–7 months), and 26 patients progressed. Conclusions: After treatment with Gefitinib, we observed maintenance of QoL in a group of patients with poor prognosis that would be expected to have a worsening QoL. Furthermore important symptoms like dyspnoea fatigue and pain in other parts, that usually afflict patients with NSCLC, showed a trend toward improvement after only one month of therapy.

This phase II study evaluated the response rate and tolerability of gemcitabine-oxaliplatin chemotherapy in non-small-cell lung cancer (NSCLC) patients. Chemonaive patients with stage IIIB or IV NSCLC received gemcitabine 1000 mg m(-2) on days 1 and 8, followed by oxaliplatin 130 mg m(-2) on day 1. Cycles were repeated every 21 days for up to six cycles. From February 2002 to May 2004, 60 patients were enrolled into the study in seven Italian institutions. We observed one complete response (1.7%) and 14 partial responses (23.3%), for an overall response rate of 25.0% (95% confidence interval, 14.7-37.9%). The median duration of response was 5.9 months (range 1.5-17.1 months). With a median follow-up of 6.7 months, median time to progressive disease and overall survival were 2.7 (range 1.9-3.4 months) and 7.3 months (range 7.2-8.6 months), respectively. The main grade 3-4 haematological toxicities were transient neutropenia in 11.7% and thrombocytopenia in 8.3% of the patients. Nausea/vomiting was the main grade 3-4 nonhaematological toxicity, occurring in 10.0% of the patients. Two (3.3%) patients developed grade 3 neurotoxicity. Our results show that gemcitabine-oxaliplatin chemotherapy is active and well tolerated in patients with advanced NSCLC, deserving further study, especially for patients not eligible to receive cisplatin.

Traumatic abdominal wall hernia (TAWH) is a muscle-fascial rupture due to a blunt direct or indirect trauma. High energy trauma is the principal cause of TAWH and they are consequence of car accidents in 50-70% and motorcycle in 15-20%. Similar trauma is described even in infant age following bicycle handlebar trauma (handlebar injuries). Surgical treatment can be urgent or secondary according to the lesions of the patient. Visceral complications secondary to TAWH are extremely rare and they are difficult to treat.

Gemcitabine (GEM) is a novel nucleoside analogue with a unique mechanism of action. Preliminary studies have shown a mild, schedule-dependent toxic profile with a broad range of MTDs and promising antitumor activity in various solid tumors. This phase I study describes the infusion length-effect relationships of low- (300 mg/m2) and high-dose (875 mg/m2) GEM, administered on days 1, 8 and 15 at 4-week intervals in a step-wise escalation of duration (or = 33%) at a starting level of 60 minutes. At least 3 patients entered each infusion-level step and 3 more cases were treated in the presence of significant toxicity. Conservative criteria for toxicity were employed, including treatment delay until recovery with infusion de-escalation in the subsequent course. Forty-seven patients (29 at low- and 18 at high-dose GEM levels) with various solid tumors, including 9 (taken as a reference) who had received the same dose levels over 30 min. entered the study. All but 9 patients (with pancreatic cancer) had been previously treated with chemotherapy and all had extensive visceral disease. A striking infusional-effect relationship was observed at both GEM dose levels. Four escalation steps were required to define the maximum tolerated infusion time (MTIT) at 6 hours for 300 mg/m2 GEM, with leucopenia being dose-limiting. At 875 mg/m2, although no limiting toxicity was observed (in spite of increased severity of leucopenia), no escalation was attempted following the 1-hour infusion, due to the limiting rate (58% of 12 patients) of toxic delay requiring shorter infusions. Toxicity was usually mild (no grade 4 event was recorded) showing the usual profile, although there was a trend towards increased non-hematologic toxicity (i.e. LFT abnormalities) as compared with the MTD previously defined using a 30-min. infusion schedule (1,370 mg/m2). Eight patients achieved a PR: 1 with NSCLC, 1 with gastric and 2 with bladder cancer at 300 mg/m2 (1 with a 3- and 3 with a 6-hour infusion) and 2 with pancreatic, 1 with cervical and another with bladder cancer at 875 mg/m2 (all but one with a 1-hour infusion). These data clearly suggest that the infusion duration is an important independent factor that influences the clinical effects of GEM. The present study not only defined the toxic profiles and the MTITs of the selected dose levels but demonstrated that GEM retained the antitumor activity at doses as small as 300 mg/m2 when given as a prolonged infusion. Further studies should clarify the underlying mechanism(s) responsible for the erratic dose-effect dose-effect relationships of GEM and establish the optimal dose-infusion level in the treatment of solid tumors.

Background Malignant pleural mesothelioma is an aggressive tumor that has a poor prognosis and is resistant to unimodal approaches. Multimodal treatment has provided encouraging results. Methods Phase II, open-label study of the combination of chemotherapy (pemetrexed 500 mg/m2+cisplatin 75 mg/m2 IV every 21 days × 3 cycles), followed by surgery (en-bloc extrapleural pneumonectomy, 3–8 weeks after chemotherapy) and hemithoracic radiation (total radiation beam 54 Gy, received 4–8 weeks post-surgery). The primary endpoint was event-free survival, defined as the time from enrollment to time of first observation of disease progression, death due to any cause, or early treatment discontinuation. Results Fifty-four treatment-naïve patients with T1-3 N0-2 malignant pleural mesothelioma were enrolled, 52 (96.3%) completed chemotherapy, 45 (83.3%) underwent surgery, 22 (40.7%) completed the whole treatment including 90-day post-radiation follow-up. The median event-free survival was 6.9 months (95%CI: 5.0-10.5), median overall survival was 15.5 months (95%CI 11.0-NA) while median time-to-tumor response was 4.8 months (95%CI: 2.5-8.0). Eighteen (33.3%) and 13 (24.1%) patients were still event-free after 1 and 2 years, respectively. The most common treatment-emergent adverse events were nausea (63.0%), anemia (51.9%) and hypertension (42.6%). Following two cardiopulmonary radiation-related deaths the protocol was amended (21 [38.9%] patients were already enrolled in the study): the total radiation beam was reduced from 54 Gy to 50.4 Gy and a more accurate selection of patients was recommended. Conclusions The combination of pemetrexed plus cisplatin followed by surgery and hemithoracic radiation is feasible and has a manageable toxicity profile in carefully selected patients. It may be worthy of further investigation. Trial registration Clinicaltrial.com registrationID #NCT00087698.