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This narrative review appraises research data on the potentially harmful effect of obesity and insulin resistance (IR) co-existence with type 1 diabetes mellitus (T1DM)-related cardiovascular (CVD) complications and evaluates possible therapeutic options.Obesity and IR have increasingly been emerging in patients with T1DM. Genetic, epigenetic factors, and subcutaneous insulin administration are implicated in the pathogenesis of this coexistence. Accumulating evidence implies that the concomitant presence of obesity and IR is an independent predictor of worse CVD outcomes. The prevalence of obesity and IR has increased in patients with T1DM. This increase can be partly attributed to general population trends but, additionally, to iatrogenic weight gain caused by insulin treatment. This association might be the missing link explaining the excess CVD burden observed in patients with T1DM despite optimal glycemic control. Data on newer agents for type 2 diabetes mellitus (T2DM) treatment are unraveling novel ways to challenge this aggravating coexistence.

Background Digital health interventions are effective for hypertension self-management, but a comparison of the effectiveness and implementation of the different modes of interventions is not currently available. This study aimed to compare the effectiveness of SMS, smartphone application, and website interventions on improving blood pressure in adults with hypertension, and to report on their reach, uptake, and feasibility. Methods In this systematic review and meta-analysis we searched CINAHL Complete, Cochrane Central Register of Controlled Trials, Ovid Embase, Ovid MEDLINE, and APA PsycInfo on May 25, 2022, for randomised controlled trials (RCTs) published in English from Jan 1, 2009, that examined the effectiveness of digital health interventions on reducing blood pressure in adults with hypertension. Screening was carried out using Covidence, and data were extracted following Cochrane's guidelines. The primary endpoint was change in the mean of systolic blood pressure. Risk of bias was assessed with Cochrane Risk of Bias 2. Data on systolic and diastolic blood pressure reduction were synthesised in a meta-analysis, and data on reach, uptake and feasibility were summarised narratively. Grading of Recommendations, Assessment, Development, and Evaluation criteria were used to evaluate the level of evidence. The study was registered with PROSPERO CRD42021247845. Findings Of the 3235 records identified, 29 RCTs from 13 regions (n=7592 participants) were included in the systematic review, and 28 of these RCTs (n=7092 participants) were included in the meta-analysis. 11 studies used SMS as the primary mode of delivery of the digital health intervention, 13 used smartphone applications, and five used websites. Overall, digital health intervention group participants had a –3·62 mm Hg (95% CI –5·22 to –2·02) greater reduction in systolic blood pressure, and a –2·45 mm Hg (–3·83 to –1·07) greater reduction in diastolic blood pressure, compared with control group participants. No statistically significant differences between the three different modes of delivery were observed for both the systolic (p=0·73) and the diastolic blood pressure (p=0·80) outcomes. Smartphone application interventions had a statistically significant reduction in diastolic blood pressure (–2·45 mm Hg [–4·15 to –0·74]); however, there were no statistically significant reductions for SMS interventions (–1·80 mm Hg [–4·60 to 1·00]) or website interventions (–3·43 mm Hg [–7·24 to 0·38]). Due to the considerable heterogeneity between included studies and the high risk of bias in some, the level of evidence was assigned a low overall score. Interventions were more effective among people with greater severity of hypertension at baseline. SMS interventions reported higher reach and smartphone application studies reported higher uptake, but differences were not statistically significant. Interpretation SMS, smartphone application, and website interventions were associated with statistically and clinically significant systolic and diastolic blood pressure reductions, compared with usual care, regardless of the mode of delivery of the intervention. This conclusion is tempered by the considerable heterogeneity of included studies and the high risk of bias in most. Future studies need to describe in detail the mediators and moderators of the effectiveness and implementation of these interventions, to both further improve their effectiveness as well as increase their reach, uptake, and feasibility.

BACKGROUND: The SARS-CoV-2 pandemic is a worldwide challenge. The CRIT-CoV-U pilot study generated a urinary proteomic biomarker consisting of 50 peptides (COV50), which predicted death and disease progression from SARS-CoV-2. After the interim analysis presented for the German Government, here, we aimed to analyse the full dataset to consolidate the findings and propose potential clinical applications of this biomarker. METHODS: CRIT-CoV-U was a prospective multicentre cohort study. In eight European countries (Austria, France, Germany, Greece, North Macedonia, Poland, Spain, and Sweden), 1012 adults with PCR-confirmed COVID-19 were followed up for death and progression along the 8-point WHO scale. Capillary electrophoresis coupled with mass spectrometry was used for urinary proteomic profiling. Statistical methods included logistic regression and receiver operating characteristic curve analysis with a comparison of the area under curve (AUC) between nested models. Hospitalisation costs were derived from the care facility corresponding with the Markov chain probability of reaching WHO scores ranging from 3 to 8 and flat-rate hospitalisation costs adjusted for the gross per capita domestic product of each country. FINDINGS: From June 30 to Nov 19, 2020, 228 participants were recruited, and from April 30, 2020, to April 14, 2021, 784 participants were recruited, resulting in a total of 1012 participants. The entry WHO scores were 1-3 in 445 (44%) participants, 4-5 in 529 (52%) participants, and 6 in 38 (4%) participants; and of all participants, 119 died and 271 had disease progression. The odds ratio (OR) associated with COV50 in all 1012 participants for death was 2·44 (95% CI 2·05-2·92) unadjusted and 1·67 (1·34-2·07) when adjusted for sex, age, BMI, comorbidities, and baseline WHO score; and for disease progression, the OR was 1·79 (1·60-2·01) when unadjusted and 1·63 (1·41-1·91) when adjusted (p

Although several liver- and inflammation-based scores to predict the clinical course of patients with coronavirus disease 2019 (COVID-19) have been evaluated, no direct comparison regarding their predictive ability has been performed.1038 patients (608 males, age 63.5 ± 17 years) hospitalized with documented COVID-19 infection to the non-ICU ward, were included retrospectively. Clinical and laboratory characteristics on admission including evaluation of Fibrosis-4 (FIB-4) score and C-Reactive Protein (CRP) to albumin ratio (CAR) were recorded.One hundred and twenty-four patients (11.9%) died during hospitalization after 8 (3-72) days. In multivariate analysis, FIB-4 (hazard ratio, 1.11; 95% confidence interval (CI), 1.034-1.19; P = 0.004), was independently associated with mortality, with very good discriminative ability (area under the receiver operating characteristic curve curve, 0.76). The patients with FIB-4amp;gt;2.67 (n = 377), compared to those with ≤2.67 (n = 661), had worse survival (log-rank 32.6; P amp;lt; 0.001). Twenty-four (6.8%) of 352 patients with possible nonalcoholic fatty liver disease (NAFLD) (defined as Hepatic Steatosis Indexamp;gt;36) died during hospitalization. In multivariate analysis, CAR was an independent risk factor (1) for mortality (hazard ratio, 1.014; 95% CI, 1.002-1.025; P = 0.021), (2) the need for high-flow nasal cannula with or without intubation (hazard ratio, 1.016; 95% CI, 1.004-1.027; P = 0.007) and (3) development of acute kidney injury (hazard ratio, 1.017; 95% CI, 1.006-1.028; P = 0.002). In addition, the patients with possible NAFLD and CARamp;gt;12 (n = 154), compared to those with CAR ≤12 (n = 198), had worse survival (log-rank 5.1; P = 0.024).FIB-4 was an independent factor for mortality with better performance compared to other liver function test- and inflammation-based scores in patients with COVID-19, while CAR was the only score independently associated with the clinical course in COVID-19 patients with possible NAFLD.

New onset or exacerbation of pre-existing psoriasis after therapeutic TNF-α inhibition is a well-described phenomenon. Over the last two decades, similar cases of paradoxical psoriasis have been reported following the administration of other biologic agents. We aimed to review all published cases of induced or exacerbated psoriasis after biologic therapy other than anti-TNF-α agents in order to further elucidate the pathophysiology of this phenomenon. A systematic literature review in the Medline database regarding any relevant case series or case reports on new onset or exacerbation of psoriasis after the administration of biologic agents targeting B cells, T cell co-stimulation, interleukin-1, interleukin-6, interleukin-17 and interleukin-12/23 was performed using appropriate key words. The literature search revealed nine articles (nine cases) of paradoxical psoriasis after ustekinumab and eight articles (nine cases) after secukinumab administration, both of which are approved therapies for psoriasis Moreover, 15 articles (23 cases) for rituximab, nine articles (12 cases) for abatacept, eight articles (nine cases) for tocilizumab, and one case report for anakinra have been published. In the majority of cases, patients had no prior history of psoriasis while 18 patients presented with exacerbation of pre-existing psoriatic lesions. Paradoxical psoriasis is not a specific adverse event of TNF-α inhibitors but is a possible side effect of any biologic agent interfering with the immune system. Awareness among physicians regarding early recognition is mandatory. Further clinical and experimental data are needed in order to unravel the pathophysiology of this unexpected phenomenon.

We read with great interest the article of Meara et al1 in your journal describing a case of chilblain-like lesions after vaccination against SARS-CoV-2. Since the start of the coronavirus disease 2019 (COVID-19) pandemic, millions of vaccine doses have been administered and their safety has been generally confirmed.

To assess non-compliance and potential changes in seasonal flu vaccination coverage before and during the Covid-19 pandemic in patients with autoimmune rheumatic diseases (ARDs). Consecutive patients with ARDs followed-up in 2 tertiary hospitals were telephone-interviewed (December 12–30, 2020) regarding seasonal flu vaccination during the 2019/20 and 2020/21 time periods. Self-reported disease flares that occurred after flu vaccination, as well as reasons for non-vaccination were recorded. One thousand fifteen patients were included. The rate of flu vaccination increased from 76% before to 83% during the COVID-19 pandemic (p = 0.0001). The rate of self-reported disease flares was

Insulin resistance (IR) is associated with a higher rate of type 1 diabetes (T1D) complications. We aimed to examine the relationship between estimated glucose disposal rate (eGDR), a readily available marker of IR in clinical practice and early predictor biomarkers of macrovascular and microvascular complications in patients with T1D.A cross-sectional study.A total of 165 consecutive patients with T1D free of cardiovascular, eye, and renal complications were included in the study from 2016 to 2020. Participants were characterized as insulin resistant if their eGDR value was ≤ 8 mg/kg/min. Pulse wave velocity (PWV) and global longitudinal strain (GLS) were used as surrogates for subclinical atherosclerosis and left ventricular systolic dysfunction (LVSD), respectively. Four previously standardized tests based on the calculation of heart rate variability (HRV) were used to evaluate subclinical cardiac autonomic neuropathy (CAN). Early nephropathy was assessed by assessing urinary albumin to creatinine ratio (ACR).The population sample (n = 165) included a majority of female patients (63%) and had a median age of 32 years (24-43), median disease duration of 14 years ( ± 9.5-21.5), a median BMI value of 23.7 kg/mIn patients with T1D, insulin resistance, as measured by eGDR, correlates well with early CVD predictors and CAN. These associations appear independent of the effects of gender, aging, and disease duration.

ObjectiveΤo report outcomes of breakthrough COVID-19 in comparison with COVID-19 in unvaccinated patients with systemic rheumatic diseases (SRDs).MethodsPatients with SRD with COVID-19 (vaccinated and unvaccinated) were included by their rheumatologists in a registry operated by the Greek Rheumatology Society in a voluntarily basis. Type, date and doses of SARS-CoV-2 vaccines were recorded, and demographics, type of SRD, concurrent treatment, comorbidities and COVID-19 outcomes (hospitalisation, need for oxygen supplementation and death) were compared between vaccinated and unvaccinated patients.ResultsBetween 1 March 2020 and 31 August 2021, 195 patients with SRD with COVID-19 were included; 147 unvaccinated and 48 vaccinated with at least one dose of a SARS-CoV-2 vaccine (Pfizer n=38 or AstraZeneca n=10). Among vaccinated patients, 29 developed breakthrough COVID-19 >14 days after the second vaccine dose (fully vaccinated), while 19 between the first and ConclusionsVaccinated patients with SRD with breakthrough COVID-19 have better outcomes compared with unvaccinated counterparts with similar disease/treatment characteristics.

Objective To describe the rate and type of adverse effects (AEs) and the frequency of disease flares after COVID-19 vaccination and to assess the reasons for vaccination hesitancy (non-vaccination) in SRD patients. Methods Telephone interviews were conducted of SRD patients consecutively enrolled (15/06/2021-1/7/2021). Participants were asked about the type of AEs and disease flare after vaccination. Reasons for vaccination hesitancy were recorded. Univariate and mutivariable analyses examined associations of demographic, clinical and other features, with occurrence of AEs, disease flare and non-vaccination. For the latter, association with negative vaccination behaviour (not influenza vaccinated for the last 2 years) and nocebo-prone behaviour (denoting AEs attributed to negative expectations [Q-No questionnaire]) was also tested. Results 561 out of 580 contacted patients were included in the study. 441/561 (78.6%) patients were vaccinated [90% (Pfizer, Moderna), 10% (Astra-Zeneca)]. AEs were reported by 148/441 (33.6%), with rates being comparable between the three vaccines. AEs were more common in females and those with chronic obstructive pulmonary disease [OR, 95% CI; females: 2.23 (1.30-3.83); COPD: 3.31 (1.24-8.83)]. Disease flare was reported in 9/441 (2%) patients. For those unvaccinated, fear that the vaccine would be harmful (53.3%), could cause disease flare (24.2%) and/or could cause thrombosis (21.7%) were the main reasons to do so. Multivariable analysis identified as independent variables for non-vaccination: nocebo-prone behaviour (OR; 95% CI, 3.88; 1.76-8.55), negative vaccination behaviour (6.56; 3.21-13.42) and previous COVID-19 infection (2.83; 1.13-7.05). Higher educational status was protective (0.49; 0.26-0.92). Conclusion No new safety signals for COVID-19 vaccination were observed. Vaccination campaign should target SRD patients with nocebo-prone and negative influenza vaccination behaviour.

To assess the possible impact conferred by co-existing variants in MEditerranean FeVer (MEFV) and other genes on systemic autoinflammatory disease (SAID) phenotype.Consecutive patients (n = 42) who underwent screening for SAIDs by next generation sequencing (NGS) targeting 26 genes, and carried at least one MEFV gene variant, were retrospectively studied. A total of 63 MEFV gene variants mainly located in exon 10 (n = 29) and exon 2 (n = 19) were identified in 21 patients with juvenile- and 21 with adult-onset disease.The candidate clinical diagnosis was Familial Mediterranean Fever (FMF) in 11, polygenic SAIDs (PFAPA, Still's disease, atypical SAPHO and inflammatory bowel disease) in 9, whereas the disease could not be clinically defined in 22 patients. Notably, 33 out of the 42 patients (79%) had at least one co-existing variants in 19 genes other than MEFV. NGS confirmed all clinical diagnoses and helped defining diagnosis in 59% of the remaining cases. Patients with undefined SAIDs (n = 9) or atypical FMF phenotype (n = 12) carried significantly more disease-causing variants in genes other than MEFV compared to patients with typical FMF (n = 9). More than one variants in these genes were significantly associated with adult-onset disease, while disease-causing variants in the same genes were also associated with an overall more severe SAID phenotype.Co-existing variants in SAID-related genes may explain the phenotypic variability of these diseases. Further studies should validate combined molecular and clinical data in order to better understand the cumulative gene dosage effect and improve the classification of these patients.

We read with great interest the preliminary German Society of Rheumatology recommendations for the management of patients with autoimmune inflammatory rheumatic diseases (AIRD) during the COVID-19 pandemic.1 As other regulatory bodies suggest2 3 patients should not discontinue their anti-rheumatic treatment because of fear.1 Herein, we investigated to which extent patients with AIRD altered their treatment during COVID-19 pandemic and whether there are any factors that affected their decision. We telephone-interviewed (14 April 2020–22 April 2020), 500 consecutive AIRD-patients followed-up in our centre and recorded the following parameters: age, sex, cohabitation, region of residence (urban, semiurban, rural), level of education (first, second, third), employment status, disease duration, current treatment and presence of co-morbidities (hypertension, hyperlipidemia, coronary heart disease, diabetes mellitus, chronic obstructive pulmonary disease (COPD), depression, anxiety). Specific questions referred to the COVID-19 pandemic period in Greece, starting on 26 February 2020, with predefined answer-options, were asked: discontinuation of any medication received for AIRDs, possible reasons that led to drug discontinuation (including fear of immunosuppresion and lack of resources/drug shortage), whether advise was received from a clinician or other sources, symptomatology compatible with COVID-19 infection, subjective assessment (on …

Background Survival advantage following trans-arterial chemoembolization (TACE) is variable in patients with hepatocellular carcinoma (HCC). We combined pre-TACE radiologic features to derive a novel prognostic signature in HCC. Methods A multi-institutional dataset of 98 patients was generated from two retrospective cohorts from United Kingdom (65%) and Italy (36%). The prognostic impact of a number baseline imaging parameters was assessed and factors significant on univariate analysis were combined to create a novel radiologic signature on multivariable analyses predictive of overall survival (OS) following TACE. Results Median OS was 15.4 months. Tumour size > 7 cm (p 7 cm, ITN and AEN identified patients with poor prognosis (p

Calcium channel blockers (CCBs) have a narrow therapeutic index, and their intake in excess is associated with a critical clinical presentation of sustained hypotension and non-cardiogenic pulmonary edema, which are difficult to treat. Unfortunately, the available treatments fail to resuscitate a significant number of patients poisoned by CCBs, rendering them the main cardiovascular drugs involved in death due to overdose. Importantly, in all cases reported until now in the literature, CCB intoxication was known at the time of patients' presentation and the medical challenge solely consisted of the therapeutic approach. In this case report, we describe our experience in treating a 72-year-old patient with recurrent episodes of sustained hypotension refractory to crystalloid and vasoconstrictor infusions. Prolonged pharmacologic support and intermittent sessions of hemofiltration induced stabilization and recovery. The results of an extensive diagnostic workup to elucidate the cause were unfruitful. The recurrent and paroxysmal nature of the clinical presentation along with its incidence after the patient left the protected setting of the hospital led the diagnostic approach to search for a possible external factor, which was shown to be, after toxicological investigation, unintentional amlodipine intoxication.

Background Acute cholecystitis is a life-threatening emergency in elderly patients. This population-based cohort study aimed to evaluate the commonly used management strategies for elderly patients with acute cholecystitis as well as resulting mortality and re-admission rates. Methods Data from all consecutive elderly patients (≥ 80 years) admitted with acute cholecystitis in England from 1997 to 2012 were captured from the Hospital Episode Statistics database. Influence of management strategies upon mortality was analyzed with adjustment for patient demographics and treatment year. Results 47,500 elderly patients were admitted as an emergency with acute cholecystitis. On the index emergency admission the majority of patients (n = 42,620, 89.7%) received conservative treatment, 3539 (7.5%) had cholecystectomy, and 1341 (2.8%) underwent cholecystostomy. In the short term, 30-day mortality was increased in the emergency cholecystectomy group (11.6%) compared to those managed conservatively (9.9%) (p

Glioblastoma multiforme (GBM) is the most common and aggressive malignancy of the central nervous system. Treatment usually involves a combination of surgical resection, chemotherapy, and radiotherapy, but ultimately this condition is incurable. Besides the dismal prognosis of GBM, financial factors have also presented challenges for advancing treatments. Taking into consideration the high cost of developing new anticancer drugs as well as the fact that GBM is a rare disease, thus further limiting financial incentive for drug development, it becomes obvious that there has been growing interest for repurposing candidates. One of the most promising drugs to repurpose for treating GBM is disulfiram (DSF). DSF is a relatively nontoxic drug used for more than sixty years in the treatment of chronic alcoholism with the ability to readily cross the blood-brain barrier. Repurposing DSF for use as an anticancer drug in general has recently become of interest because of its preclinically described anticancer effects against various human cancers. Interestingly, a number of these effects were shown to be copper (Cu)-dependent. The purpose of this paper was to review the existing literature surrounding preclinical and clinical data on the effects of DSF -alone or in combination with Cu- in GBM. In addition, we present the first case of a GBM patient safely treated with DSF/Cu combination along with standard therapy exhibiting remarkably increased progression-free (PFS) and overall survival (OS).

Laparoscopic sleeve gastrectomy has become one of the most commonly performed bariatric operations. It is essentially a restrictive bariatric operation; however, a series of hormonal changes occurring postoperatively contribute to decreased appetite and reduced food intake.This is a literature review of recent articles published on Pubmed, Medline and Google Scholar databases in English.Although, laparoscopic sleeve gastrectomy is commonly performed worldwide, there is still a lack of standardization regarding the surgical technique. Standardizing the surgical technique is essential in order to minimize postoperative complications and offer patients the best long-term weight loss.Laparoscopic sleeve gastrectomy appears to be an effective bariatric operation. It is relatively easy to perform, well tolerated by the patients and very effective regarding long-term excessive weight loss and resolution of the comorbidities, with minimum nutritional deficiencies.

Background Sleeve gastrectomy (SG) is increasingly indicated as a stand-alone procedure for the treatment of clinically severe obesity. Our objective was to present the outcomes of SG in relation to weight loss, resolution of co-morbidities, and procedural morbidity/mortality for ≤5 years postoperatively. The study was conducted at a university hospital, bariatric referral center. Methods From January 2005 to December 2010, 208 patients underwent SG at our institution. Per standard protocol, SG was the sole surgery indicated for weight reduction in patients with a body mass index of ≤50 kg/m2 who were not “sweet-eaters” and had no symptoms of gastroesophageal reflux disease. The study endpoints were weight loss, perioperative and late morbidity/mortality, and clinical improvement in co-morbidities and consequential nutritional deficiencies. Results SG was performed laparoscopically in 203 of the patients. The mean age and body mass index was 34.3 ± 10.3 years and 43.2 ± 2.8 kg/m2, respectively. No deaths were recorded. Early morbidity (≤30 d) was 9.6%, chiefly owing to staple line closure leaks, and late morbidity was 4.8%. A mean excess weight loss of 71.1% was documented in 90 (89.4%) of 106 patients, available for follow-up after 3 years. The excess weight loss slowly declined to 57.6% in 21 (77.7%) of 27 patients at 5 years of follow-up. No major metabolic deficiencies were apparent. Statistically significant improvements in pre-existing hypertension, diabetes mellitus, and dyslipidemia were achieved. After laparoscopic SG, gastroesophageal reflux disease symptoms developed in 9.8% of patients within the first postoperative year but lessened over time to 7.4% at the 5-year mark. Conclusions SG is a reproducible procedure associated with significant weight reduction, resolution of obesity-related co-morbidities, and minor nutritional deficits at 5 years of follow-up. Laparoscopic SG can thus be safely used as the sole surgical treatment of clinically severe obesity (body mass index ≤50 kg/m2). The chief complication of postoperative leakage can be managed nonoperatively in most patients.

Gallstone ileus is an uncommon complication of gallstone disease. It occurs in elderly patients in up to 25% of the cases. The management of gallstone ileus remains controversial. Open surgery has been the mainstay of treatment, but laparoscopic surgery has recently been used. In this study we report a case of an 87-year-old female patient with gallstone ileus who has been managed totally laparoscopically, detailing the technique and discussing the advantages of the laparoscopic approach with a review of the literature.The pneumoperitoneum was established with a Veress needle. A three-port approach (one 5-mm and two 10-mm trocars) and a 30° 10-mm laparoscope were used. The site of obstruction was 5 cm below the ligament of Treitz, and a single gallstone was identified. A 3-cm longitudinal enterotomy was created just above the site where the gallstone was located. An 8-cm-long gallstone was extracted. The enterotomy was closed transversely in a single layer of two sets of continuous sutures.The procedure was safely performed with all the advantages of minimally invasive surgery. Previous studies often described laparoscopically assisted procedures for the treatment of gallstone ileus, using a small abdominal incision. In recent years, some reports have been published on the efficacy of the totally laparoscopic approach in the management of gallstone ileus.Totally laparoscopic management of gallstone ileus could be safe and effective with suggested benefits for the elderly patients.

Over the past 14 years, we have used different malabsorptive bariatric operations to treat super-obesity. We compared the efficacy and safety of our preferred procedure for the last 8 years with previous methods used in super-obese. Our first procedure was distal Roux-en-Y gastric bypass (distal RYGBP) (gastric pouch 15 ± 5 mL, 80 cm biliopancreatic limb, 100 cm common limb [CL]). The second was distal RYGBP with short alimentary limb (distal RYGBP-sAL) (gastric pouch 15 ± 10 mL, alimentary limb [AL] 250 cm, CL 100 cm). Our preferred procedure for the past 8 years has been biliopancreatic diversion with RYGB and long limbs (BPD-RYGB-LL) (gastric pouch 40 ± 10 mL, AL 400 cm, CL 100 cm). Seventy-five patients underwent distal RYGBP, 44 distal RYGBP-sAL, and 841 BPD-RYGB-LL. Eight years postoperatively, the mean BMIs were 39.0, 29.4, and 29.2, respectively. The greatest reduction of 47.6% was achieved with BPD-RYGB-LL (distal RYGBP 30.6%; distal RYGBP-sAL 43.1%). Mean excess weight loss was 51.3% for distal RYGBP, 76.5% for distal RYGBP-sAL, and 80.9% for BPD-RYGB-LL. Six patients died at the early postoperative period. Sixteen patients died during the first eight postoperative years, of whom significantly more were after distal RYGBP-sAL (P = 0.0003). Complications were significantly more frequent after distal RYGBP-sAL (P = 0.001). All procedures led to rapid and sustained resolution of major comorbidities in almost all patients affected. Metabolic and nutritional deficiencies were similar and manageable. Our variant of biliopancreatic diversion (BPD-RYGB-LL) results in substantial and sustained weight loss in super-obese, without compromising safety.

Laparoscopic Roux-en-Y gastric bypass (LRYGB) is currently the gold standard bariatric procedure for the treatment of morbid obesity. Laparoscopic sleeve gastrectomy (LSG) is a relatively innovative procedure which has been increasingly applied lately as a sole bariatric procedure. A randomized trial was conducted in a Greek population to evaluate perioperative safety and 3-years results.Sixty patients with body mass index (BMI) ≤ 50 Kg/m(2) were randomized to LRYGB or LSG. Patients were monitored for 3 years postoperatively and throughout the study period weight loss, in terms of percent excess weight loss (%EWL), early and late complications, improvement of obesity related comorbidities and nutritional deficiencies were compared between groups.There was no death in either group and there was no significant difference in early (10% after LRYGB and 13% after LSG, P 0.05) and late morbidity (10% in each group). Weight loss was significantly better after LSG in the first years of the study and at 3 years %EWL reached 62% after LRYGB and 68% after LSG (p = 0.13). There was no significant difference in the overall improvement of comorbidities. Nutritional deficiencies occurred at the same rate in the two groups except to vitamin B(12) deficiency which was more common after LRYGB (P = 0.05).LSG and LRYGB are equally safe and effective in the amelioration of comorbidities, while LSG is associated with fewer postoperative metabolic deficiencies, without the need of supplementation. Furthermore, LSG is a promising bariatric procedure, equally effective to LRYGB at 3 years follow up on weight reduction.

Objective Insomnia is frequently underrecognized in medical wards; therefore, we assessed the prevalence and explored medical and psychological variables associated with insomnia. Method The Athens Insomnia Scale and the Hospital Anxiety and Depression Scale (HADS) were completed in 235 inpatients along with demographic data, admission diagnosis, lifetime psychiatric diagnosis and prescribed psychotropics. Results The overall insomnia prevalence was 37%. Logistic regression showed that HADS anxiety and depression cases and patients with infections were more likely to have insomnia (OR 24.2, 6.1 and 5.4, respectively). Conclusions Patients with depressive and mainly anxiety symptoms are more likely to experience insomnia in medical wards. Patients with infections are also likely to have insomnia, independently of depressive and anxiety symptoms, and appropriate interventions should be applied.

The International Subarachnoid Aneurysm Trial (ISAT) concluded that "there is currently no reason to doubt that the reduction of dependent survival or death after endovascular coiling seen in all patients in the ISAT cohort should not be valid in the elderly". We feel that this generalization requires further investigation to assess its validity.We studied the impact of treatment era and independent risk factors for outcome in 179 consecutive elderly (or =70 years) aneurysmal subarachnoid hemorrhage (aSAH) patients admitted to Kuopio University Hospital either between 1983 and 1992 (Era I, n = 56), prior to the introduction of endovascular management, or between 1995 and 2004 (Era II, n = 123) when the endovascular treatment was established at our institute. Altogether 150 patients underwent occlusive aneurysm treatment, 47 clipping in the Era I as against 49 clipping, 49 endovascular therapy, and five combination therapy in the Era II.The 12-month survival (n = 179) did not improve from the Era I to the Era II. The proportion of good outcome (GOS IV-V) after occlusive therapy (n = 150) was equal in the Era I and Era II (n = 27/47; 57% vs. n = 56/103; 54%). In multivariate logistic regression analysis, independent predictors of poor outcome were age, poor grade (HuntHess IV-V), hydrocephalus, hypertension, and intraventricular hemorrhage, but not the mode of occlusive therapy (microsurgical vs. endovascular)Clinical severity of the SAH was the most significant predictor of outcome. Integration of coil treatment in clinical practice has not improved the overall outcome of aSAH in the elderly at our institute.

Laparoscopy has been widely accepted among surgeons for the diagnosis and management of acute abdominal conditions. In this study, we aim to evaluate and summarize the experience in laparoscopic procedures, both diagnostic and interventional, for emergency nontraumatic abdominal conditions, in a tertiary academic center.From June 2005 to June 2009, a total of 1414 patients were subjected to a variety of emergency procedures at the university hospital of Patras and 540 of these patients were managed laparoscopically (38.2%). Indications for operations in the laparoscopic group were abdominal pain mimicking appendicitis in 229 patients (42.4%), acute cholecystitis in 248 patients (45.9%), gastroduodenal perforated ulcer in 14 patients (2.6%), small bowel obstruction in 24 patients (4.4%), and nonspecific abdominal pain in 25 patients (4.6%).Diagnosis was established in 530 patients (98.2%) and definitive laparoscopic treatment was offered to 514 patients (95.2%). The conversion rate was 2.2%. Total mortality was 1.1% and total morbidity was 7.9%.Laparoscopic approach to abdominal emergency provides high diagnostic accuracy and therapeutic options. Surgical experience, optimal procedural timing, and appropriate patient selection criteria diminish perioperative mortality and morbidity, and are associated with nominal conversion.

Background & Aims There are a number of prognostic scores in hepatocellular carcinoma (HCC), none of which is optimal in predicting overall survival (OS) in the individual patient, particularly in intermediate stage disease, where patients are not surgically treatable but may qualify for a wide range of palliative interventions. We evaluated the prognostic role of a biochemical algorithm, the Kings Score (KS), in the palliative setting of care. Methods We used the algorithm [age x AST x INR]/platelet count to derive the KS. Full clinical data including Barcelona Clinic Liver Cancer (BCLC) stage were studied in a training set of 97 patients from the UK. Independent predictors of survival identified in multivariate analysis were validated in an independent cohort of 766 patients from Japan and Italy. Results In both training and validation sets, KS was confirmed as an independent predictor of OS (P

SummaryBackground Transarterial chemoembolisation (TACE) is a standard treatment for unresectable, intermediate stage hepatocellular carcinoma (HCC). Survival after TACE, however, can be highly variable, with no suitable biomarker predicting therapeutic outcome. The inflammation-based index (IBI) has previously been shown to independently predict overall survival (OS) in all stages of HCC. Aim To explore the prognostic ability of IBI as a predictor of survival after TACE. Methods Baseline staging, biochemical and clinicopathological features including IBI were studied in a derivation set of 64 patients undergoing TACE for intermediate stage HCC. Dynamic changes in IBI before and after TACE were studied as predictors of survival using both a univariate and multivariate Cox regression model and further validated in two independent patient cohorts from Korea (n = 76) and Japan (n = 577). Results Pre-treatment IBI predicted for OS in the derivation set (P = 0.001). Other univariate predictors of OS included radiological response to TACE (P 5 cm (P = 0.05) and AFP ≥400 (P

Background. Single-incision laparoscopic surgery is a rapidly emerging approach to gallbladder disease. Methods. From February 2009 to September 2010, 60 patients were subjected to single-incision laparoscopic cholecystectomy. In all the patients, a 12-mm incision was made in the umbilicus and a 2-trocar technique was applied. Gallbladder was suspended with 2 sutures and the procedure was accomplished with standard partly reusable laparoscopic instruments. Results. In all, 41 women (68.3%) and 19 men (31.7%) were enrolled in this study. Mean age was 50.7 years (range = 17-72 years), mean body mass index was 26.2 kg/m2 (range = 18.3-37.7 kg/m2) and mean operative time was 52.6 minutes (range = 30-120 minutes). No mortality or morbidity was recorded and hospital stay was less than 24 hours. At follow-up visits, no complications were recorded and cosmesis was excellent. Conclusion. Single-incision laparoscopic cholecystectomy can be safely performed with conventional instrumentation with minimal cost.

Background Delayed ischemic neurologic deficit (DIND) is a serious complication of acute aneurysmal subarachnoid hemorrhage (aSAH). Although oral nimodipine is accepted as standard care for the prevention of DIND, the intravenous route is preferred by several centers. In the present study we compared the clinical efficacy between enteral and intravenous nimodipine after aSAH. Methods A total of 171 aSAH patients were randomly assigned to either the enteral (84 patients) or the intravenous (87 patients) nimodipine group and were compared regarding the incidence of DIND, number of new ischemic lesions on 12-month brain magnetic resonance image, and clinical outcome 12 months after aSAH as assessed by Glasgow Outcome scale, modified Rankin scale, and Karnofsky scale. Health-related quality of life was also assessed by the 15D questionnaire 12 months after aSAH. Results The incidence of DIND did not differ significantly between the groups (20% in the enteral versus 16% in the intravenous group, P = 0.61), whereas no differences were observed, neither in the number of new ischemic lesions (34% in both groups, P = 0.99), nor in the clinical outcome 12 months after aSAH ( P = 0.34 for Glasgow Outcome scale, P = 0.74 for modified Rankin scale, and P = 0.71 for Karnofsky scale). The mean 15D health-related quality of life sums were also similar in the 2 groups ( P = 0.43). Conclusions Our pilot study suggested no differences in the clinical efficacy of enteral and intravenous nimodipine after aSAH. However, a much larger phase III clinical trial would be needed to show or exclude meaningful clinical differences.

OBJECTIVE: To evaluate the rate of complications and the risk factors in relation to the extent of surgery in patients undergoing thyroidectomy in a tertiary university center. DESIGN: Data were collected retrospectively from 2,043 consecutive patients who underwent thyroid surgery for various thyroid diseases at the University Hospital of Patras, Greece, between January 1996 and December 2007. recurrent laryngeal nerve palsy (rLNP) and hypoparathyroidism were set as the primary end points, while hematoma and wound infection were set as the secondary endpoints. rESULTS: Total, near-total and subtotal thyroidectomy was performed in 1,149, 777 and 117 patients, respectively. Transient rLNP occurred in 34 (1.6%) and permanent in 19 (0.9%) patients. Multivariate logistic regression analysis showed that extended resection (Or-odds ratio-1.6), Graves’ disease (Or 2.7), thyroiditis (Or 2.1), recurrent goiter (Or 2.3) and thyroid malignancy (Or 1.7) were all independent risk factors for transient rLNP, whereas Graves’ disease (Or 2.2) and recurrent goiter (Or 1.7) emerged as independent risk factors for permanent rLNP. The rates of transient and permanent hypoparathyroidism were 27.8% and 4.8%, respectively. Multivariate analysis for transient hypoparathyroidism revealed that the extent of surgical resection (Or 2.2), Graves’ disease (Or 2.1), recurrent goiter (Or 1.7), female gender (Or 1.5) and specimen weight (Or 1.6) were independent predictors. However, the extent of surgical resection (Or 2.7), Graves’ disease (Or 1.8), recurrent goiter (Or 1.5) and malignant disease (Or 1.5) were independent risk factors for permanent hypoparathy roidism. Postoperative wound infection and hematoma occurred in 6 (0.3%) and 27 (1.3%) patients, respectively. No correlation was observed between wound infection or postoperative hemorrhage and the extent of surgery. CONCLUSIONS: Despite the higher morbidity, total thyroidectomy is emerging as an attractive surgical option even for benign thyroid disease due to the risk of subclinical (occult) malignancy, the possibility of goiter relapse as well as of the increased risk of complications following reoperation.

Bariatric procedures are effective in the life-long treatment of clinically severe obesity, but they are technically demanding and have known complications. The present study presents mortality and morbidity with different procedures from the prospective 15-year bariatric database of the University Hospital of Patras in Greece. From June 1994 through December 2008, 1,162 morbidly obese patients underwent various bariatric procedures at our institution (35 vertical banded gastroplasties, 151 laparoscopic sleeve gastrectomies, 90 open and 137 laparoscopic Roux-en-Y gastric bypasses, 699 biliopancreatic diversions with long limbs, and 50 reoperations). Postoperative metabolic deficiencies and causes of early and late morbidity for various bariatric procedures were compared by using the z-test for the comparison of proportions. Logistic regression analysis was used to model the occurrence of early and late death and complications. Total mortality was 1.81% (early 0.6%, intermediate 0.26%, late 0.95%). No significant predictors for early death were found, but age (odds ratio (OR), 1.077; 95% confidence interval (CI), 1.024–1.133; P = 0.004) and BMI (OR, 1.156; 95% CI, 1.023–1.306; P = 0.02) were predictors for late death. Early and late morbidity were 8% and 27.71%, respectively. The total leakage incidence was 1.98% and was significantly higher (P

Giant cell tumors (GCTs) of the bone are rare, usually benign but locally aggressive neoplasms that primarily occur in the epiphyses of long bones. They seldom develop in the cranium; when they do, they involve principally the sphenoid and temporal bones. These tumors usually affect young adults, and few reports in children have been published. Primary malignant GCTs of the skull are even more uncommon. The 3 published cases all involved adults over 40 years of age. Herein, the authors present a case of a highly aggressive primary malignant GCT of the posterior fossa in a 5-week old preterm infant. One month after the gross-total resection of the tumor found in the bone, the infant's condition rapidly deteriorated and she died. Magnetic resonance imaging and postmortem examination revealed a tumor larger than it had been before the operation, with expansion toward the brain. To the best of the authors' knowledge, this is the youngest patient reported with a primary malignant GCT of the skull, and actually the first case in a pediatric patient. In addition, the extremely high growth rate of the tumor in the postoperative period renders this case the most aggressive primary malignant GCT of the cranium described so far.

Among various human CYPs, CYP2E1 is of particular interest because of its involvement in the metabolic activation of many low molecular mass procarcinogens. CYP2E1 induction, which may be a consequence of genetic polymorphism or/and gene induction by xenobiotics, is the first step leading to the development of certain chemically-mediated cancers. The aim of this review is to outline the current knowledge on chemically-induced cancers through activation by CYP2E1, with emphasis on the association between polymorphisms of the CYP2E1 gene and incidence of different neoplasias.Literature searches of MEDLINE (1966 to July 2009) for English articles in CYP2E1-induced carcinogenesis were conducted.CYP2E1 genetic polymorphisms leading to enhanced CYP2E1 gene transcription have been associated with increased risk of development of malignant tumours, through increased biotransformation of procarcinogens. Likewise, long-term intake of CYP2E1 inducers, such as ethanol, isoniazid, various solvents and chemicals, also increase the probability of developing malignancy, especially for carriers of certain CYP2E1 alleles.Genetic screening for CYP2E1 'carcinogenic' polymorphisms and CYP2E1 phenotype determination of susceptible subjects, as well as the development of effective CYP2E1 inhibitors, could be a future perspective towards prevention of CYP2E1-mediated cancers.

Neuroendoscopy is considered a safe treatment option for intracranial arachnoid cysts. However a variety of complications has been reported after such interventions. Here we present the first case of a chronic subdural hematoma two months after the combined treatment of a supracellar arachnoid cyst with endoscopic third ventriculostomy and cyst fenestration.

A case of a 33-year-old man presented with symptoms of dramatic deterioration of the level of consciousness because of a recurrence of a previously aspirated and irradiated craniopharyngioma is described. The tumor had grown enormously in dimensions and was extending in the region of hypothalamus, third ventricle and brain stem, with signs of local compression and obstructive hydrocephalus. Radical surgical excision, despite the size and the location of the lesion, was the therapy of choice. The surgical technique is described. We conclude that in expert hands, microsurgery aiming at total removal should be the therapeutic option for the treatment of recurrent as well as primary craniopharyngiomas.

Increased activity of CYP2E1 has been associated with increased risk of chemically-mediated cancers, through enhanced activation of a variety of procarcinogens. In this context, inhibition of CYP2E1 is potentially of significance in xenobiotic toxicity. The aim of the present study was to test the hypothesis that quinacrine inhibits hepatic CYP2E1. For this purpose, disulfiram (75 mg/kg i.p) as an inhibitor and isoniazid (100 mg/kg i.p) as an inducer of CYP2E1, as well as quinacrine (50 mg/kg i.p) were administered to Wistar rats and the hepatic activity of CYP2E1 was measured. The expression of CYP2E1 was further assessed by Western blot analysis. As expected, disulfiram inhibited, while isoniazid induced the activity and expression of the enzyme. Interestingly, treatment with quinacrine resulted in a significant decrease of CYP2E1 activity and expression. To investigate any similarities in the inhibition of CYP2E1 by quinacrine and disulfiram, molecular modeling techniques were adopted and revealed that quinacrine molecule anchors inside the same binding pocket of the protein where disulfiram is also attached. Finally, as assessed by the sister chromatid exchanges (SCE) assay, quinacrine was demonstrated to reduce the mutagenic effects of the tobacco-specific N-nitrosamine 4-(methyl nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), which is known to be converted to active mutagen in the liver principally through CYP2E1. We suggest that these antimutagenic effects of quinacrine could be possibly attributed, at least in part, to its ability to block the bioactivation of NNK, mainly by the inhibition of CYP2E1. Our results, even preliminary, indicate that quinacrine as an inhibitor of CYP2E1 might be protective against chemically-induced toxicities such as NNK-induced mutagenicity. Arch Toxicol

Eur J Obstet Gynecol Reprod Biol

Increased activity of CYP2E1 has been associated with increased risk of chemically-mediated cancers, through enhanced activation of a variety of procarcinogens. In this context, inhibition of CYP2E1 is potentially of significance in xenobiotic toxicity. The aim of the present study was to test the hypothesis that quinacrine inhibits hepatic CYP2E1. For this purpose, disulfiram (75 mg/kg i.p) as an inhibitor and isoniazid (100 mg/kg i.p) as an inducer of CYP2E1, as well as quinacrine (50 mg/kg i.p) were administered to Wistar rats and the hepatic activity of CYP2E1 was measured. The expression of CYP2E1 was further assessed by Western blot analysis. As expected, disulfiram inhibited, while isoniazid induced the activity and expression of the enzyme. Interestingly, treatment with quinacrine resulted in a significant decrease of CYP2E1 activity and expression. To investigate any similarities in the inhibition of CYP2E1 by quinacrine and disulfiram, molecular modeling techniques were adopted and revealed that quinacrine molecule anchors inside the same binding pocket of the protein where disulfiram is also attached. Finally, as assessed by the sister chromatid exchanges (SCE) assay, quinacrine was demonstrated to reduce the mutagenic effects of the tobacco-specific N-nitrosamine 4-(methyl nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), which is known to be converted to active mutagen in the liver principally through CYP2E1. We suggest that these antimutagenic effects of quinacrine could be possibly attributed, at least in part, to its ability to block the bioactivation of NNK, mainly by the inhibition of CYP2E1. Our results, even preliminary, indicate that quinacrine as an inhibitor of CYP2E1 might be protective against chemically-induced toxicities such as NNK-induced mutagenicity.

Pressure dressing (PD) after modified radical mastectomy (MRM) for breast cancer is investigated here as an easy-to-apply method to reduce seroma formation and subsequent need for clinical care.Two hundred mastectomized patients who were treated with PD on the skin flaps and the axilla immediately postoperatively (group A) were compared with a similar non-PD group (B). Surgical technique and perioperative care were the same. Drains were removed when drain output was reduced to 30 ml per day, or on postoperative day 8 regardless of output.Mean time with drains kept in situ was 4.9 and 5.5 days in group A and B, respectively. Five (2.5%) patients in group A and 16 (8%) in group B developed seromas after the removal of the drains. In total, 9 seroma needle aspirations were performed in group A and 26 in group B. Differences were statistically significant.Our findings are supportive of PD as an effective, cheap and easy-to-apply method for the reduction (a) of the time with drains in situ after MRM, (b) of the number of patients developing seromas and (c) of the seroma aspirations. This can potentially reduce further complications, needed medical care and cut expenditure.

Bariatric surgery is currently the most effective treatment in morbidly obese patients, leading to durable weight loss.In this prospective double blind study, we aim to evaluate and compare the effects of laparoscopic Roux-en-Y gastric bypass (LRYGBP) with laparoscopic sleeve gastrectomy (LSG) on body weight, appetite, fasting, and postprandial ghrelin and peptide-YY (PYY) levels.After randomization, 16 patients were assigned to LRYGBP and 16 patients to LSG. Patients were reevaluated on the 1st, 3rd, 6th, and 12th postoperative month. Blood samples were collected after an overnight fast and in 6 patients in each group after a standard 420 kcal mixed meal.Body weight and body mass index (BMI) decreased markedly (P0.0001) and comparably after either procedure. Excess weight loss was greater after LSG at 6 months (55.5% +/- 7.6% vs. 50.2% +/- 6.5%, P = 0.04) and 12 months (69.7% +/- 14.6% vs. 60.5% +/- 10.7%, [P = 0.05]). After LRYGBP fasting ghrelin levels did not change significantly compared with baseline (P = 0.19) and did not decrease significantly after the test meal. On the other hand, LSG was followed by a marked reduction in fasting ghrelin levels (P0.0001) and a significant suppression after the meal. Fasting PYY levels increased after either surgical procedure (Por = 0.001). Appetite decreased in both groups but to a greater extend after LSG.PYY levels increased similarly after either procedure. The markedly reduced ghrelin levels in addition to increased PYY levels after LSG, are associated with greater appetite suppression and excess weight loss compared with LRYGBP.

The so-called “serotonin syndrome” (SS) is a potentially serious condition of central and peripheral serotonergic hyperstimulation. It is caused by the administration of single drugs or combinations of drugs that elevate synaptic levels of serotonin. It can arise following both therapeutic doses and overdoses, while the most serious cases are usually caused by an unintended synergism between a selective serotonin reuptake inhibitor (SSRI) and one or several other medications possessing serotonergic activity, such as monoamine oxidase (MAO) inhibitors.1 However, sometimes these other drugs are not known to possess serotonergic activity, making diagnosis more difficult. Furazolidone is one of the synthetic antimicrobial nitrofurans used in the treatment of diarrhoea or enteritis caused by bacteria. It may also be useful in treating traveller’s diarrhoea, typhoid fever, cholera and salmonella infections. Moreover, due to its anti-H. pylori activity,2 it has been used in China for more than 20 years in the treatment of peptic ulcers. In countries such as Brazil that have a large population with low socioeconomic levels and high bacterial resistance to metronidazole, furazolidone is believed to be a valuable alternative for patients who need retreatment for H. pylori eradication.3 As early as the 1960s, furazolidone was shown to be an inhibitor of MAO activity.4 In support of these results, we recently demonstrated for the first time that furazolidone produces a tremendous increase in brain serotonin levels in Wistar rats.5 Thus, it seems that furazolidone possess serotonergic activity and its combination with other serotonergic agents could, at least in theory, result in SS. However, this is not widely known and there have been few follow-up studies, making it possible that SS associated with furazolidone could go unrecognised. Labelling for furazolidone typically warns about interactions with MAO inhibitors and “tranquilisers”, but not SSRIs; in addition, no warnings are given regarding the possibility of SS with these potential interacting drugs. In conclusion, I suggest that clinicians should be aware of the serotonergic properties of furazolidone, which should be prescribed very cautiously in patients under therapy with SSRIs, MAO inhibitors, or other medications that have a high probability of inducing SS. Due to the potentially serious nature of this condition, it seems prudent that physicians always monitor patients receiving combinations of serotonergic drugs and be alert to the possibility of “serotonergic duplication”. Retrospective case studies should be undertaken to look for furazolidone-induced SS. Moreover, basic research efforts in animal models are needed to better clarify the interactions of furazolidone with other serotonergic agents. In the meantime, physicians, pharmacists and clinical pharmacologists should keep the possibility of SS in mind when faced with patients taking furazolidone and who present with characteristic findings; anyone with such cases should publish them in Medline-referenced journals, ideally with free internet full-text access, so that the information can be disseminated world-wide.

In order to further improve the toxicity profile and the anticancer effect of chlorambucil (CBL), we have synthesized a new estrone D-lactam steroidal ester of CBL (ESBL). The aim of this study was to investigate the in vitro activity of ESBL against primary breast carcinoma (BC) cells of operable tumors in comparison with CBL. Cells derived from fresh tumor sections that were obtained from 28 postmenopausal women with ductal BC were treated with CBL and ESBL. Apoptotic cells were distinguished from viable ones with flow cytometric methods. ESBL generated a significantly higher rate of cell apoptosis and cytotoxicity than CBL. ESBL cytotoxic effect demonstrated a significant positive weak to moderate dose-dependent correlation with the ER expression. ESBL produced antineoplastic activity superior to CBL on primary BC tumors in vitro. Moreover, a docking study on the binding interactions of ESBL with the ligand binding domain (LBD) of estrogen receptor-alpha (ERalpha) was investigated. ESBL was found to be positioned inside the binding cavity with its steroidal moiety, whereas the alkylating moiety protruded out of receptor's pocket.

The sensitivity of breast neoplasms to hormonal control provides the basis of novel investigational treatments with steroidal alkylators. An androsterone D-lactam steroidal ester, the 3beta-hydroxy-13alpha-amino-13,17-seco- 5alpha-androstan-17-oic-13,17-lactam, p-bis(2-chloroethyl)amino phenyl acetate (lactandrate) was synthesized and tested for antitumor activity against six human breast cancer cell lines in vitro and against two murine and one xenograft mammary tumors in vivo. A docking study on the binding interactions of lactandrate with the ligand-binding domain (LBD) of estrogen receptor-alpha (ERalpha) was inquired. In vitro testing of lactandrate cytostatic and cytotoxic activity was performed on T47D, MCF7, MDA-MB-231, BT-549, Hs578T, MDA-MB-435 breast adenocarcinoma human cell lines. In vivo testing was performed on two murine mammary tumors, the MXT tumor and CD8F1 adenocarcinoma, as well as on human mammary carcinoma MX-1 xenograft. Molecular modeling techniques were adopted to predict a possible location and interaction mode of the molecule into LBD. Lactandrate induced significantly high antitumor effect against all tested in vitro and in vivo models. The cell lines with positive ER expression found to be significantly more sensitive to lactandrate. Moreover, lactandrate found to be positioned inside the binding cavity with its steroidal moiety, whilst the alkylating moiety protrudes out of receptor's pocket. Lactandrate produced important anticancer activity on breast cancer in vitro and in vivo. Some correlation between ER and lactandrate effect was demonstrated. Docking studies provide the basis for the structure-based design of improved steroidal alkylating esters for the treatment of estrogen-related cancers.

Male breast cancer represents approximately 1% of all breast cancer cases. Due to the low disease incidence, even the largest reported studies have included a limited number of cases. Therefore, there is a lack of extensive experience as far as the etiology, therapeutic modalities and prognosis of this disease are concerned.