Predictors of recurrence following laparoscopic minor hepatectomy for hepatocellular carcinoma in the UK.

AIMS: Minor hepatectomy, which is increasingly carried out laparoscopically (LLR), is a cornerstone of curative treatment for hepatocellular carcinoma (HCC). The majority of relevant publications however originate from regions with endemic viral hepatitis. Although the incidence of HCC in the UK is increasing, little is known about outcomes following LLR. METHODS: Consecutive patients undergoing minor (involving ≤2 segments) LLR or open resection (OLR) at our institute between 2014 and 2021 were compared. Selection from a plethora of factors potentially impacting on overall (OS) and disease free survival (DFS) was optimised with Lasso regression. To enable analysis of patients having repeat resection, multivariate frailty modelling was utilised to calculate hazard ratios (HR). RESULTS: The analysis of 111 liver resections included 55 LLR and 56 OLR. LLR was associated with a shorter hospital stay (5 ± 2 vs. 7 ± 2 days; p < 0.001) and a lower comprehensive complication index (4.43 vs. 9.96; p = 0.006). Mean OS (52.3 ± 2.3 vs. 49.9 ± 3.0 months) and DFS (33.9 ± 3.4 vs. 36.5 ± 3.6 months; p = 0.59) were comparable between LLR and OLR, respectively (median not reached). Presence of mixed cholangiocarcinoma/HCC, satellite lesions and AFP level predicted OS and DFS. In addition tumour size was predictive of DFS. CONCLUSIONS: In the studied population minor LLR was associated with shorter hospital stay and fewer complications while offering non-inferior long-term outcomes. A number of predictors for disease free survival have been elucidated that may aid in identifying patients with a high risk of disease recurrence and need for further treatment.

First-in-human study of LY3039478, an oral Notch signaling inhibitor in advanced or metastatic cancer.

Background: Deregulated Notch signaling due to mutation or overexpression of ligands and/or receptors is implicated in various human malignancies. γ-Secretase inhibitors inhibit Notch signaling by preventing cleavage of transmembrane domain of Notch protein. LY3039478 is a novel, potent Notch inhibitor decreases Notch signaling and its downstream biologic effects. In this first-in-human study, we report the safety, pharmacokinetic (PK) profile, pharmacodynamic effects, and antitumor activity of LY3039478 in patients with advanced or metastatic cancer. Methods: This phase I, open-label, multicenter, nonrandomized, and dose-escalation phase study determined and confirmed the recommended phase II dose of LY3039478 (oral dose: 2.5-100 mg, thrice weekly (TIW) on a 28-day cycle). The primary objectives are to determine (part A) and confirm (part B) a recommended phase II dose that may be safely administered to patients with advanced or metastatic cancer, and secondary objectives include evaluation of safety, tolerability, PK parameters, and preliminary antitumor activity of LY3039478. Results: A total of 110 patients were treated with LY3039478 monotherapy between 31 October 2012 and 15 July 2016. Dose-limiting toxicities were thrombocytopenia, colitis, and nausea. Most adverse events were gastrointestinal. The recommended phase II dose was 50 mg TIW, because of its better tolerability compared with 75 mg. The PKs of LY3039478 appeared dose proportional. Pharmacodynamic data indicate an ∼80% inhibition of plasma Aß, and >50% inhibition of Notch-regulated genes hairy and enhancer of split-1, cyclin D1, and Notch-regulated ankyrin repeat at 45-100-mg dose. Clinical activity (tumor necrosis, metabolic response, or tumor shrinkage) was observed in patients with breast cancer, leiomyosarcoma, and adenoid cystic carcinoma. Conclusion: Potent inhibition of Notch signaling by LY3039478 was well tolerated at doses associated with target engagement, and demonstrated evidence of clinical activity in heavily pretreated patients. Further investigation with LY3039478 as monotherapy and in combination with targeted agent or chemotherapy is ongoing. Clinicaltrials.gov ID: NCT01695005.

Phase III randomized study of second line ADI-PEG 20 plus best supportive care versus placebo plus best supportive care in patients with advanced hepatocellular carcinoma.

Background: Arginine depletion is a putative target in hepatocellular carcinoma (HCC). HCC often lacks argininosuccinate synthetase, a citrulline to arginine-repleting enzyme. ADI-PEG 20 is a cloned arginine degrading enzyme-arginine deiminase-conjugated with polyethylene glycol. The goal of this study was to evaluate this agent as a potential novel therapeutic for HCC after first line systemic therapy. Methods and patients: Patients with histologically proven advanced HCC and Child-Pugh up to B7 with prior systemic therapy, were randomized 2 : 1 to ADI-PEG 20 18 mg/m2 versus placebo intramuscular injection weekly. The primary end point was overall survival (OS), with 93% power to detect a 4-5.6 months increase in median OS (one-sided α = 0.025). Secondary end points included progression-free survival, safety, and arginine correlatives. Results: A total of 635 patients were enrolled: median age 61, 82% male, 60% Asian, 52% hepatitis B, 26% hepatitis C, 76% stage IV, 91% Child-Pugh A, 70% progressed on sorafenib and 16% were intolerant. Median OS was 7.8 months for ADI-PEG 20 versus 7.4 for placebo (P = 0.88, HR = 1.02) and median progression-free survival 2.6 months versus 2.6 (P = 0.07, HR = 1.17). Grade 3 fatigue and decreased appetite occurred in <5% of patients. Two patients on ADI-PEG 20 had ≥grade 3 anaphylactic reaction. Death rate within 30 days of end of treatment was 15.2% on ADI-PEG 20 versus 10.4% on placebo, none related to therapy. Post hoc analyses of arginine assessment at 4, 8, 12 and 16 weeks, demonstrated a trend of improved OS for those with more prolonged arginine depletion. Conclusion: ADI-PEG 20 monotherapy did not demonstrate an OS benefit in second line setting for HCC. It was well tolerated. Strategies to enhance prolonged arginine depletion and synergize the effect of ADI-PEG 20 are underway. Clinical Trial number: www.clinicaltrials.gov (NCT 01287585).

Effect of Obesity on Hemoglobin Concentration.

Obesity is a disorder of body weight regulatory systems characterized by an accumulation of excess body fat. World Health Organization recommended that 66% of deaths now occur in developing countries and recognizes obesity as a leading risk factor. Obesity is associated with chronic, low grade, systemic inflammation. The inflammatory state play a causal role in the development of insulin resistance, type 2 diabetes and the metabolic syndrome. This descriptive type of cross sectional study will design to evaluate the relation between obesity with hemoglobin concentration. One hundred obese and 100 normal weight persons from both sexes, aged between 25 to 60 years will be selected from Mymensingh Medical College, Mymensingh and locality from July 2014 to January 2016. Data are collected through a simple questionnaire after informed consent taken. The result was calculated and analyzed by using SPSS (statistical package for social science, version 11.5). Statistical significance of difference between two groups were evaluated by unpaired Student's 't' test. Data were expressed as Mean±SE. P value less than 0.05 was taken as the level of significance. Anthropometric measurements such as height and weight were taken in meter and kilogram respectively. Pulse, systolic and diastolic blood pressure was measured by aneroid sphygmomanometer (ALPK2, Japan), laboratory analysis of hemoglobin was done by Cyanmethemoglobin Method. In this study we found that hemoglobin concentration is significantly increased in both male and female obese persons.

Phase 1 dose-escalation study of S-222611, an oral reversible dual tyrosine kinase inhibitor of EGFR and HER2, in patients with solid tumours.

BACKGROUND: S-222611 is a reversible inhibitor of EGFR, HER2 and HER4 with preclinical activity in models expressing these proteins. We have performed a Phase 1 study to determine safety, maximum tolerated dose (MTD), pharmacokinetic profile (PK) and efficacy in patients with solid tumours expressing EGFR or HER2. PATIENTS AND METHODS: Subjects had advanced tumours not suitable for standard treatment, expressing EGFR or HER2, and/or with amplified HER2. Daily oral doses of S-222611 were escalated from 100mg to 1600 mg. Full plasma concentration profiles for drug and metabolites were obtained. RESULTS: 33 patients received S-222611. It was well tolerated, and the most common toxicities, almost all mild (grade 1 or 2), were diarrhoea, fatigue, rash and nausea. Only two dose-limiting toxicities occurred (diarrhoea and rash), which resolved on interruption. MTD was not reached. Plasma exposure increased with dose up to 800 mg, exceeding levels eliciting pre-clinical responses. The plasma terminal half-life was more than 24h, supporting once daily dosing. Responses were seen over a wide range of doses in oesophageal, breast and renal tumours, including a complete clinical response in a patient with HER2-positive breast carcinoma previously treated with lapatinib and trastuzumab. Four patients have remained on treatment for more than 12 months. Downregulation of pHER3 was seen in paired tumour biopsies from a responding patient. CONCLUSIONS: Continuous daily oral S-222611 is well tolerated, modulates oncogenic signalling, and has significant antitumour activity. The recommended Phase 2 dose, based on PK and efficacy, is 800 mg/day.

Functional imaging techniques in hepatocellular carcinoma.

Novel biological therapies, including tyrosine kinase inhibitors such as sorafenib, improve the survival of patients with unresectable hepatocellular carcinoma. However, assessment of therapeutic efficacy remains challenging with conventional imaging techniques such as ultrasonography, CT or MRI that predominantly rely on size change to detect a treatment response. A beneficial tumour effect may go unrecognized in some patients who do not show tumour shrinkage and conversely, some patients may be maintained on treatment that is not active. This paper explores the use of functional imaging methods that are showing promise in the assessment of hepatocellular carcinoma.

Effect of nutrition education on exclusive breastfeeding for nutritional outcome of low birth weight babies.

BACKGROUND/OBJECTIVES: Low birth weight (LBW), defined as the body weight at birth of less than 2500 g, is a major public health problem in Bangladesh, where 37% of the babies are born with LBW. The objective of this study is to see the impact of nutrition education on growth of LBW babies with early initiation and exclusive breastfeeding compared to control group. SUBJECTS/METHODS: A total of 184 LBW babies and their mothers who attended the Maternal Care and Health Training Institute and Dhaka Medical College Hospital were randomly allocated to either intervention or control group. Enrollment of the study population started in May 2008 and was completed in October 2008. Nutrition education was given to mothers twice weekly for 2 months, on initiation of breastfeeding within 1 h, exclusive breastfeeding and increasing their dietary intake. Nutritional status of LBW babies was assessed for length and weight every 2 weeks. Data were analyzed using SPSS/Window's version 12. Comparison of mean of data was done using standard Student's t-test. RESULTS: Mean initial body weight and length of LBW babies were similar in both groups (2261±198 g vs 2241±244 g, P=0.535 and 43.0±1.3 cm vs 43.0±1.7 cm, P=0.77). Body weight and length of the LBW babies after 2 months increased significantly (3620±229 g vs 3315±301 g, P<0.001 and 50.2±1.3 cm vs 48.7±1.6 cm, P<0.001). It was found that the intervention group suffered less from respiratory illness compared with the control group (39% vs 66%, P<0.001). The rate of early initiation of breastfeeding was also significantly higher with nutrition intervention (59.8% vs 37.2%, P<0.001). Exclusive breastfeeding rate was significantly higher in intervention group (59.8% vs 37%, P=0.003). CONCLUSIONS: The present study showed that weight and length gain of LBW babies significantly increased by breastfeeding and nutrition education. Therefore, nutrition education on breastfeeding proves to be a strong tool to reduce the high risk of malnutrition and mortality of the LBW babies.

A retrospective analysis of clinical outcome of patients with chemo-refractory metastatic breast cancer treated in a single institution phase I unit.

BACKGROUND AND METHODS: Novel approaches to treat chemo-refractory metastatic breast cancer (MBC) are currently under investigation. This retrospective series reviews the outcome of 70 MBC patients who have participated in 30 phase I trials at the Royal Marsden Hospital from 2002 to 2009. RESULTS: The median treatment lines before phase I trial entry for MBC was 5 (range: 1-12 lines). The overall response rate was 11.4% (95% CI: 4.0-18.9%) and the clinical benefit rate at 4 months was 20% (95% CI: 10.6-29.3). The median time to progression was 7.0 weeks (95% CI: 6.4-7.5) and median overall survival was 8.7 months (95% CI: 7.6-9.8) from start of first phase I treatment. No patients discontinued trial because of treatment-related toxicities. Abnormal lactate dehydrogenase, serum albumin <35 mg per 100 ml, >or=5 previous treatment lines, liver metastases and Eastern Cooperative Group performance status >or=2 at study entry were significantly associated with poor overall survival in multivariate analysis. CONCLUSION: This retrospective analysis provides evidence that patients with MBC tolerate phase I clinical trials and a significant proportion of patients with chemo-refractory disease, particularly those with triple-negative or Her2-positive breast cancer, may benefit from treatment.

Chemotherapy with 5-fluorouracil, cisplatin and streptozocin for neuroendocrine tumours.

BACKGROUND: The role of chemotherapy for neuroendocrine tumours remains controversial and there is no standard regimen. METHOD: We report the outcome for a consecutive series of chemonaive patients with metastatic or locally advanced neuroendocrine tumours treated with a combination of 5-fluorouracil (500 mg m(-2)), cisplatin (70 mg m(-2)) and streptozocin (1000 mg m(-2)) (FCiSt) administered three weekly for up to six cycles. Patients were assessed for radiological response, toxicity and survival. RESULTS: In the 79 patients assessable for response, treatment with FCiSt was associated with an overall response rate of 33% (38% for pancreatic primary sites and 25% for non-pancreatic primary sites). Stable disease occurred in a further 51%, with progression in 16%. The median time to progression was 9.1 months and median overall survival was 31.5 months. The most common grade 3-4 toxicity was neutropaenia (28% patients) but grade 3-4 infection was rare (7%). The most frequent non-haematological grade 3-4 toxicity was nausea and vomiting (17%). Prognostic factors included Ki-67, mitotic index, grade and chromogranin A, whereas response to chemotherapy was predicted by mitotic index, grade and alpha-fetoprotein. CONCLUSIONS: FCiSt is an effective regimen for neuroendocrine tumours with an acceptable toxicity profile. Grade and mitotic index are the best predictors of response.

Persistence of low serum iron and high total iron binding capacity in pregnant women.

A cross sectional descriptive type of study was done in 98 women of reproductive age. Among them 25 were in control group of non pregnant women and 73 were pregnant women of 1st, 2nd and 3rd trimester of pregnancy with and without iron supplementation. The period of study was July 2004 to June 2005. The main objective of our study was to compare serum iron and total iron binding capacity in pregnant and non pregnant women. In present study serum iron was significantly increased in 2nd and 3rd trimester of pregnancy that was supplemented with iron when compared with the same category of women who were not supplemented with iron. On the other hand serum total iron binding capacity (TIBC) was significantly increased in 3rd trimester of pregnancy that was not supplemented with iron when compared with the same category of women who were supplemented with iron. It is evident that the significantly low serum iron and high TIBC in pregnant women is due in part to dietary iron deficiency. Therefore, iron therapy in pregnancy is helpful to maintain the serum iron and TIBC nearer to that of non pregnant normal women.

Concentration dependent structural ordering of poloxamine 908 on polystyrene nanoparticles and their modulatory role on complement consumption.

Adsorption of poloxamine 908, a tetrafunctional polyethylene oxide (PEO)-polypropylene oxide ethylenediamine block copolymer, onto the surface of monodispersed polystyrene nanoparticles (232 +/- 0.33 nm) follows a bimodal pattern. Initially, the isotherm follows a Langmuir profile with a plateau observable over a very narrow equilibrium poloxamine concentration (0.0018-0.0031 mM). The isotherm then begins to rise again, reaching a final plateau at equilibrium poloxamine concentrations above 0.0089 mM. Similarly, the profile of the adsorbed layer thickness of poloxamine on the surface of nanoparticles is bimodal. The first plateau corresponds to a thickness of 4.6 +/- 0.07 nm, which occurs over the same range of poloxamine concentrations as in the initial plateau of the adsorption isotherm. The second plateau corresponds to a thickness of 9.53 +/- 0.32 nm, observable at a minimum poloxamine concentration of 0.0067 mM. By using a calculated radius of gyration of a PEO chain in poloxamine as 3.1 nm, these observations reflect dynamic changes in the arrangement of surface projected PEO chains; a mushroom-like conformation at the first plateau region of the adsorption isotherm, followed by a transition into a brush-like conformation. These conformational changes are also reflected in rheological studies; the apparent viscosity of nanoparticles in which the PEO chains are in mushroom conformation is considerably higher than particles displaying the brush conformation. Further, atomic force microscopy studies (height profile and phase lag measurements) corroborated that the proposed poloxamine concentration dependent transition of surface associated PEO chains from mushroom to brush appearance is conserved when nanoparticles are dried under ambient conditions. Finally, we compared the influence of the surface PEO characteristics on complement consumption in human serum. Our results show complement-activating nature of all poloxamine-coated nanoparticles. However, complement consumption is reduced substantially with particles bearing a minimum of 11448 poloxamine molecules on their surface, thus demonstrating the importance of PEO surface density as well as brush conformation in suppressing complement consumption. This relationship between surface characteristics of poloxamine nanoparticles and their in vivo performance is discussed.

Improving the outcome of patients with castration-resistant prostate cancer through rational drug development.

Castration-resistant prostate cancer (CRPC) is now the second most common cause of male cancer-related mortality. Although docetaxel has recently been shown to extend the survival of patients with CRPC in two large randomised phase III studies, subsequent treatment options remain limited for these patients. A greater understanding of the molecular causes of castration resistance is allowing a more rational approach to the development of new drugs and many new agents are now in clinical development. Therapeutic targets include the adrenal steroid synthesis pathway, androgen receptor signalling, the epidermal growth factor receptor family, insulin growth factor-1 receptor, histone deacetylase, heat shock protein 90 and the tumour vasculature. Drugs against these targets are giving an insight into the molecular pathogenesis of this disease and promise to improve patient quality of life and survival. Finally, the recent discovery of chromosomal translocations resulting in the upregulation of one of at least 3 ETS genes (ERG, ETV1, ETV4) may lead to novel agents for the treatment of this disease.

Synthesis and in vitro modeling and characterization of self-assembling drug conjugates for targeted medicinal application.

A number of conjugates tend to self-associate in a transient or permanent fashion and this has formed the basis of considerable intense scientific and commercial investigation over recent years. This article considers a variety of strategic formulations, their flaws and advantages. Working practices and groundbreaking developmental activities within the sphere of self-assembling drug conjugates are also reviewed.

Effects of dietary tamarind on cholesterol metabolism in laying hens.

An experiment was conducted to evaluate the potential for dietary tamarind to alter serum and egg yolk cholesterol concentrations and overall performance in different layer strains. Thirty, 43-wk-old, Hisex Brown, ISA Brown, Lohmann Brown, Starcross Brown, Babcock B-300, and Starcross-579 strains (5 hens per strain) were fed diets supplemented with 0 (control), 2, 4, 6, or 8% oven-dried tamarind for 6 wk. Egg production, egg mass, and efficiency of feed utilization followed a quadratic response with a maximum when the diet contained 2% tamarind and a minimum when 8% tamarind was fed (P < 0.05). There were no differences (P > 0.05) among strains for egg production, egg weight, yolk weight, egg mass, feed consumption, or feed efficiency. Yolk weight increased linearly (P < 0.05) with increasing levels of dietary tamarind in wk 1, 2, and 3 as well as when averaged over 6 wk. Egg yolk cholesterol concentrations were not affected by dietary tamarind. Serum cholesterol concentrations, however, decreased quadratically with increasing levels of dietary tamarind (P < 0.05). It was concluded that 2% supplemental dietary tamarind could decrease serum cholesterol concentrations and increase layer performance.

Role of Mg2+ in the interaction of anticancer antibiotic, chromomycin A3 with DNA: does neutral antibiotic bind DNA in absence of the metal ion?

Antitumor antibiotic, Chromomycin A3 (CHR), inhibits DNA replication and transcription via reversible interaction with double stranded DNA with GC-base specificity. The interaction, at and above physiological pH, requires the presence of bivalent metal ions, such as Mg2+. Anionic antibiotic does not bind DNA in the absence of Mg2+. In this paper we have examined the structural potential of neutral CHR at pH 5.2 to bind DNA in the absence of Mg2+. We have demonstrated the ability of the neutral antibiotic to bind DNA by means of different spectroscopic techniques and evaluated the necessary thermodynamic parameters for elucidation of the molecular basis of recognition. The results are compared with the scenario when Mg2+ is present in the system, because the ultimate aim of these studies is to elucidate the role of Mg2+ in CHR-DNA recognition. Neutral CHR binds to Mg2+ with lesser affinity than its anionic form. Spectroscopic features of the drug and its Mg2+ complex indicate self association of the antibiotic in the absence and presence of Mg2+. GC-base specificity of the drug and its Mg2+ complex are retained at pH 5.2, though the modes of recognition of DNA by the two ligands are different. Minor groove width of DNA plays a role in the accommodation of the ligand(s) during the GC base specific recognition while positive charge of Mg2+ in CHR:Mg2+ complex further facilitates the association. Relatively lower affinity of the neutral drug and its Mg2+ complex for DNA can be ascribed to the self association of these ligands in the absence of DNA.

Effect of cyproterone acetate on the proteinase activities of adult rat testis and epididymis.

PIP: The in vivo and in vitro effects of cyproterone acetate (CA), an antiandrogenic compound, on the proteinase activities in epididymal and testicular spermatozoa in male albino rats was studied. CA was injected intramuscularly at a dose of 50 mg/kg daily for 10, 20, and 30 days. The testis and epididymis were homogenized and submitted for enzyme assay. The in vitro experments involved the incubation of supernatents from centrifuged testis and epididymis for 30 minutes with CA. Proteinases were assayed using acid-denatured hemoglobin as substrate. Acid proteinase activities increased in both testis and epididymis, but the inhibition of neutral and alkaline proteinase activities was greater in epididymis than testis with both long- and short-term treatment with CA. It is suggested that CA inhibits the maturational processes in the epididymis rather than spermatogenesis in the testis.^ieng