Comparison of outcomes following surgical resection, percutaneous ablation or stereotactic body radiation therapy in early-stage, solitary and small (≤3 cm) treatment-naïve hepatocellular carcinoma.

INTRODUCTION: Stereotactic body radiation therapy (SBRT) is associated with high local control rates in hepatocellular carcinoma (HCC). This study reports the outcomes of SBRT compared to surgical resection (SR) and percutaneous ablation (PA) for treatment-naïve, solitary HCCs ≤3 cm. METHODS: This was a retrospective study of patients with BCLC stage 0/A HCC with a single ≤3 cm lesion, treated with curative intent between 2016 and 2020. SBRT was used for patients considered unsuitable for SR or PA. The co-primary endpoints were progression-free survival (PFS) and overall survival (OS). The secondary endpoints were treatment-related clinical toxicity rates and local control (LC) rates. RESULTS: There were 112 patients included in this study. SBRT was delivered in 36 patients (32.1%), 51 had PA (45.5%) and 25 underwent SR (22.3%). Median follow-up was 23 months (range, 3-60 months) from diagnosis. The 3-year PFS and OS were 67% and 69% following SBRT, 55% and 80% following PA, and 85% and 100% following SR, respectively. Patients in the SR cohort had significantly better 3-year PFS and OS compared to SBRT and PA groups (p = 0.03 and p = 0.04, respectively). There was no significant difference in PFS (p = 0.15) or OS (p = 0.23) between SBRT and PA treated patients. The 3-year LC rate for the entire cohort was 98%. CONCLUSIONS: In patients with treatment-naïve, early-stage solitary HCCs ≤3 cm, SBRT was associated with comparable PFS, OS and LC outcomes to PA. SBRT should be considered as a curative intent therapy to avoid treatment stage migration in this favourable prognostic cohort of patients.

Definitive Stereotactic Body Radiation Therapy in Early-Stage Solitary Hepatocellular Carcinoma: An Australian Multi-Institutional Review of Outcomes.

AIMS: Standard curative options for early-stage, solitary hepatocellular carcinoma (HCC) are often unsuitable due to liver dysfunction, comorbidities and/or tumour location. Stereotactic body radiation therapy (SBRT) has shown high rates of local control in HCC; however, limited data exist in the treatment-naïve, curative-intent setting. We report the outcomes of patients with solitary early-stage HCC treated with SBRT as first-line curative-intent therapy. MATERIALS AND METHODS: A multi-institutional retrospective study of treatment-naïve patients with Barcelona Clinic Liver Cancer stage 0/A, solitary ≤5 cm HCC, Child-Pugh score (CPS) A liver function who underwent SBRT between 2010 and 2019 as definitive therapy. The primary end point was freedom from local progression. Secondary end points were progression-free survival, overall survival, rate of treatment-related clinical toxicities and change in CPS >1. RESULTS: In total, 68 patients were evaluated, with a median follow-up of 20 months (range 3-58). The median age was 68 years (range 50-86); 54 (79%) were men, 62 (91%) had cirrhosis and 50 (74%) were Eastern Cooperative Oncology Group 0. The median HCC diameter was 2.5 cm (range 1.3-5) and the median prescription biologically effective dose with a tumour a/b ratio of 10 Gy (BED10) was 93 Gy (interquartile range 72-100 Gy). Two-year freedom from local progression, progression-free survival and overall survival were 94.3% (95% confidence interval 86.6-100%), 59.5% (95% confidence interval 46.3-76.4%) and 88% (95% confidence interval 79.2-97.6%), respectively. Nine patients (13.2%) experienced grade ≥2 treatment-related clinical toxicities. A rise >1 in CPS was observed in six cirrhotic patients (9.6%). CONCLUSION: SBRT is an effective and well-tolerated option to consider in patients with solitary, early-stage HCC. Prospective, randomised comparative studies are warranted to further refine its role as a first-line curative-intent therapy.

The influence of non-thermal technologies on color pigments of food materials: An updated review.

The color of any food is influenced by several factors, such as food attributes (presence of pigments, maturity, and variety), processing methods, packaging, and storage conditions. Thus, measuring the color profile of food can be used to control the quality of food and examine the changes in chemical composition. With the advent of non-thermal processing techniques and their growing significance in the industry, there is a demand to understand the effects of these technologies on various quality attributes, including color. This paper reviews the effects of novel, non-thermal processing technologies on the color attributes of processed food and the implications on consumer acceptability. The recent developments in this context and a discussion on color systems and various color measurement techniques are also included. The novel non-thermal techniques, including high-pressure processing, pulsed electric field, ultrasonication, and irradiation which employ low processing temperatures for a short period, have been found effective. Since food products are processed at ambient temperature by subjecting them to non-thermal treatment for a very short time, there is no possibility of damage to heat-sensitive nutrient components in the food, any deterioration in the texture of the food, and any toxic compounds in the food due to heat. These techniques not only yield higher nutritional quality but are also observed to maintain better color attributes. However, suppose foods are exposed to prolonged exposure or processed at a higher intensity. In that case, these non-thermal technologies can cause undesirable changes in food, such as oxidation of lipids and loss of color and flavor. Developing equipment for batch food processing using non-thermal technology, understanding the appropriate mechanisms, developing processing standards using non-thermal processes, and clarifying consumer myths and misconceptions about these technologies will help promote non-thermal technologies in the food industry.

Nano/micro-plastics: Sources, trophic transfer, toxicity to the animals and humans, regulation, and assessment.

Being in an era of revolutionized production, consumption, and poor management of plastic waste, the existence of these polymers has resulted in an accumulation of plastic litter in nature. With macro plastics themselves being a major issue, the presence of their derivatives like microplastics which are confined to the size limitations of less than 5mm has ascended as a recent type of emergent contaminant. Even though there is size confinement, their occurrence is not narrowed and is extensively seen in both aquatic and terrestrial extents. The vast incidence of these polymers causing harmful effects on various living organisms through diverse mechanisms such as entanglement and ingestion have been reported. The risk of entanglement is mainly limited to smaller animals, whereas the risk associated with ingestion concerns even humans. Laboratory findings indicate the alignment of these polymers toward detrimental physical and toxicological effects on all creatures including humans. Supplementary to the risk involved with their presence, plastics also proceed as carters of certain toxic contaminants complemented during their industrial production process, which is injurious. Nevertheless, the assessment regarding the severity of these components to all creatures is comparatively restricted. This chapter focuses on the sources, complications, and toxicity associated with the presence of micro and nano plastics in the environment along with evidence of trophic transfer, and quantification methods.

Outcomes Following Hypofractionated Stereotactic Radiotherapy to the Cavity After Surgery for Melanoma Brain Metastases.

AIMS: Hypofractionated stereotactic radiotherapy (HSRT) to the cavity after surgical resection of brain metastases improves local control. Most reported cohorts include few patients with melanoma, a population known to have high rates of recurrence and neurological death. We aimed to assess outcomes in patients with melanoma brain metastases who received HSRT after surgery at two Australian institutions. MATERIALS AND METHODS: A retrospective analysis was carried out including patients treated between January 2012 and May 2020. HSRT was recommended for patients with melanoma brain metastases at high risk of local recurrence after surgery. Treatment was delivered using appropriately commissioned linear accelerators. Routine follow-up included surveillance magnetic resonance imaging brain every 3 months for at least 2 years. Primary outcomes were overall survival, local control, incidence of radiological radionecrosis and symptomatic radionecrosis. RESULTS: There were 63 cavities identified in 57 patients. The most common HSRT dose prescriptions were 24 Gy in three fractions and 27.5 Gy in five fractions. The median follow-up was 32 months in survivors. Local control was 90% at 1 year, 83% at 2 years and 76% at 3 years. Subtotal brain metastases resection (hazard ratio 12.5; 95% confidence interval 1.4-111; P = 0.0238) was associated with more local recurrence. Overall survival was 64% at 1 year, 45% at 2 years and 40% at 3 years. There were 10 radiological radionecrosis events (16% of cavities) during the study period, with 5% at 1 year and 8% at 2 years after HSRT. The median time to onset of radiological radionecrosis was 21 months (range 6-56). Of these events, three became symptomatic (5%) during the study period at a median time to onset of 26 months (range 21-32). CONCLUSION: Cavity HSRT is associated with high rates of local control in patients with melanoma brain metastases. Subtotal resection strongly predicts for local recurrence after HSRT. Symptomatic radionecrosis occurred in 5% of cavities but increased to 8% of longer-term survivors.

Diagnostic and prognostic significance of prostate specific antigen and serum interleukin 18 and 10 in patients with locally advanced prostate cancer: a prospective study.

BACKGROUND: Prostate cancer is one of the most common cancers afflicting men today. Prostate biopsy, an invasive procedure is generally used for diagnoses but attempts are being made to find accurate and precise non-invasive biomarkers. Diagnostic accuracy of prostate specific antigen (PSA) has been well documented. Serum interleukin-18 (IL-18) and interleukin-10 (IL-10) have shown their diagnostic ability in other cancers but not investigated well in prostate cancer. This study, thus determines the diagnostic and prognostic significance of PSA, IL-18 and IL-10 prospectively in patients with carcinoma prostate. METHODS: A total of 149 patients, aged 40-84 yrs were investigated during April 2007 to July 2010 and recruited for this study after Institutional ethical approval. Of the total of 149 patients, 71 had biopsy proven prostate cancers (TNM stage: T2=17, T3=26 and T4=28) and 78 clinical benign prostate hyperplasia (BPH). Peripheral blood samples of all patients and 71 age matched control subjects were obtained at baseline and estimation of PSA, IL-18 and IL-10 was done by enzyme linked immunosorbent assay (ELISA). Carcinoma prostate patients were followed for three years. Data were analyzed with ANOVA, ROC curve analysis and survival analysis. RESULTS: The baseline levels of PSA, IL-18 and IL-10 in all groups of carcinoma prostate were found to be significantly (p<0.01) higher than both Control and BPH. The levels of IL-18 and IL-10 also found to be elevated significantly in stage T3 (p<0.05) and T4 (p<0.01) as compared to stage T2. The levels especially of IL-18 is found to be well associated with progression of the disease of various groups (r=0.84, p<0.01). In contrast, IL-10 showed significant direct association with progression of carcinoma (r=0.84, p<0.01) while inverse relation with survival duration (r=-0.48, p<0.01) and survival rate (χ2=8.98, p=0.0027; Hazard ratio=0.37, 95% CI=0.18-0.69). CONCLUSIONS: Study concluded that serum IL-18 has potential to be a better diagnostic marker with higher specificity and sensitivity and IL-10 may be valuable as a prognostic marker than PSA in carcinoma prostate.

Pars plana vitrectomy with posterior iris claw implantation for posteriorly dislocated nucleus and intraocular lens.

We evaluated the safety and efficacy of pars plana vitrectomy (PPV) with primary posterior iris claw intraocular lens (IOL) implantation in cases of posterior dislocation of nucleus and IOL without capsular support. This was a retrospective interventional case series. Fifteen eyes underwent PPV with primary posterior iris claw IOL implantation performed by a single vitreoretinal surgeon. The main outcome measures were changes in best corrected visual acuity and anterior and posterior segment complications. A total of 15 eyes were included in this study. Eight had nucleus drop, three had IOL drop during cataract surgery and four had traumatic posterior dislocation of lens. The final postoperative best corrected visual acuity was 20/60 or better in 11 patients. This procedure is a viable option in achieving good functional visual acuity in eyes without capsular support.

Oxidative stress in non-small cell lung cancer patients after chemotherapy: association with treatment response.

UNLABELLED: Levels of lipid peroxidation, nitric oxide and glutathione, as well as superoxide dismutase activity were evaluated in non-small cell lung cancer patients before and after chemotherapy. Oxidative stress was shown to influence treatment efficacy and survival of these patients. BACKGROUND AND OBJECTIVE: The aim of this study was to assess the level of oxidative stress after chemotherapy in non-small cell lung cancer patients, and its association with treatment response and survival. METHODS: Two hundred and three previously untreated non-small cell lung cancer patients and 150 healthy subjects were selected for the study. Patients received cisplatin+etoposide, and were followed for up to six cycles, for evaluation of oxidative stress. Blood levels of lipid peroxidation products (LPO), glutathione (GSH) and nitric oxide (NO), and superoxide dismutase (SOD) activity were measured at day 0 and after the third and sixth cycles of chemotherapy. Response and survival were measured at the end of follow up. Survival was estimated by the Kaplan-Meier method using the log-rank test. RESULTS: In the patients, pretreatment levels of LPO and NO were low, while GSH and SOD levels were high compared with those after the third and sixth cycles of chemotherapy. Among the 203 patients, there were 51 deaths, 82 non-responders and 70 responders at the end of the sixth cycle. Overall mean survival was higher among responders than non-responders (24.6 vs 21.2 weeks, P<0.01). The hazard ratio was 2.4 (95% CI: 1.3-3.77). Pretreatment levels of oxidative stress were similar among responders and non-responders (P>0.05). After the third and sixth cycles of chemotherapy, LPO and NO levels were low (P<0.05 or P<0.01) and GSH levels and SOD activity were high (P<0.05 or P<0.01) in responders as compared with non-responders. CONCLUSIONS: In lung cancer patients, oxidative stress increased and anti-oxidant enzymes decreased as the disease progressed. Chemotherapy may suppress oxidative stress and decreased anti-oxidant enzyme activity in responders as compared with non-responders. These effects may contribute to improved survival among responders.

Smoking intensity, oxidative stress and chemotherapy in nonsmall cell lung cancer: a correlated prognostic study.

Cigarette smoking is a well known environmental risk factor for lung cancer; furthermore it can also enhance lung carcinogenesis by free radical mediated reactions. In addition smoking affects the rates of metabolism of several drugs and may contribute to poor cancer survival. The purpose of the present work, therefore, was to see the relationship of different smoking intensities with oxidative stress and survival after platinum based chemotherapy in non-small cell lung cancer (NSCLC). The oxidative stress levels (LPO, NO, SOD, and GSH) of 144 control subjects and 203 advanced stage NSCLC patients were assessed at day '0', after the 3rd and 6th cycle of chemotherapy. Pack year (PY) was stratified in groups (1-20, 21-50, > 50) for further analysis. Groups were compared using repeated measured ANOVA, while survival curves were compared by Kaplan-Meier methods. Oxidative stress levels of smokers were significantly high (p < 0.01 or p < 0.05) as compared to non-smoker at pretreatment, after the 3rd cycle and 6th cycle of chemotherapy but not well correlated with the PY exposures. Overall mean survival of smoker patients were significantly low when compared to non-smokers. The survival of > 50 PY group was significantly lowered (p < 0.01) as compared to others PY groups, indicating that survival after chemotherapy in smoker NSCLC patients may be dependent on their PY exposures. In conclusion, smoking is a bad prognostic factor in lung cancer therapy, besides its role in oxidative stress, and poor survival. Therefore, this factor can be used in patient selection for chemoprevention.

MDA-7/IL-24, a novel tumor suppressor/cytokine is ubiquitinated and regulated by the ubiquitin-proteasome system, and inhibition of MDA-7/IL-24 degradation enhances the antitumor activity.

Steady-state protein levels are determined by the balance between protein synthesis and degradation. Protein half-lives are determined primarily by degradation, and the major degradation pathways involve either lysosomal destruction or an ATP-dependent process involving ubiquitination to target proteins to the proteosome. Studies have shown that multiple tumor-suppressor proteins are ubiquitinated and degraded by the 26S proteasome. In the present study, we investigated whether the tumor suppressor/cytokine melanoma differentiation-associated gene-7/interleukin-24 gene (MDA-7/IL-24) protein is ubiquitinated and its degradation controlled by the proteasome. Treatment of ovarian (2008) and lung (H1299) tumor cells with adenoviral delivery of mda-7 (Ad-mda7) or Ad-mda7 plus the proteosome inhibitor MG132 showed that MDA-7 protein expression was dependent upon proteosome activity. Western blot and immunoprecipitation analyses verified that the MDA-7 protein was ubiquitinated and that ubiquitinated-MDA-7 levels were increased in MG132-treated cells. These results were confirmed using small interfering RNA (siRNA)-mediated knockdown of ubiquitin. Furthermore, ubiquitinated MDA-7 protein was degraded by the 26S proteasome, as MDA-7 accumulation was observed only when cells were treated with MG132 but not with lysosome or protease inhibitors. Inhibition of the catalytic beta-5 subunit of the 20S proteasome using siRNA resulted in MDA-7 protein accumulation. Finally, treatment of tumor cells with Ad-mda7 plus the proteasome inhibitor bortezomib resulted in increased tumor cell killing. Our results show that MDA-7/IL-24 is ubiquitinated and degraded by the 26S proteasome. Furthermore, inhibition of MDA-7 degradation results in enhanced tumor killing, identifying a novel anticancer strategy.

Estimating probabilities of diabetes mellitus using neural networks.

Classification problems are often encountered in medical diagnosis. This paper presents an introduction to classification theory and shows how artificial neural networks can be used for classification. We also map out a bootstrapped procedure for interval estimation of posterior probabilities. The entire procedure is illustrated using the diabetes mellitus data in Pima Indians.

Using neural networks to predict the onset of diabetes mellitus.

Classification is an important decision making tool, especially in the medical sciences. Unfortunately, while several classification procedures exist, many of the current methods fail to provide adequate results. In recent years, artificial neural networks have been suggested as an alternative tool for classification. Here, we use neural networks to predict the onset of diabetes mellitus in Pima Indian women. The modeling capabilities of neural networks are compared to traditional methods like logistic regression and to a specific method called ADAP, which has been used to predict diabetes. The results indicate that neural networks are indeed a viable approach to classification. Furthermore, we attempt to provide a basis upon which neural networks can be used for variable selection in statistical modeling.

Development of lipofuscin-like fluorescence in the retinal pigment epithelium in response to protease inhibitor treatment.

Experiments were conducted to determine whether photoreceptor outer segment components contain precursors for lipofuscin fluorophores that accumulate in the retinal pigment epithelium (RPE) during senescence. Intravitreal injection of the lysosomal protease inhibitor leupeptin caused a rapid accumulation of inclusions with lipofuscin-like autofluorescence in the RPE of albino rats. These inclusions appeared to be derived from photoreceptor outer segments, which are normally phagocytosed and degraded by the RPE. The tripeptide leu-gly-gly, which is similar to leupeptin except that it does not inhibit proteolysis, had no effect on RPE autofluorescent pigment content. Likewise, netilmicin, a purported inhibitor of lysosomal phospholipases, did not enhance autofluorescent pigment deposition in the RPE. These findings are consistent with other experiments suggesting that RPE age-pigment fluorophores are derived from molecular components of the photoreceptor outer segments. The effect of leupeptin suggests that outer segment proteins may be among the precursors for these fluorophores. The RPE appears to differ from other cell types that accumulate lipofuscin in that the majority of the precursors for this pigment in the RPE are taken up by phagocytosis rather than being generated within the cells themselves.