Dietary Methionine and Total Sulfur Amino Acid Restriction in Healthy Adults.

OBJECTIVES: Dietary restriction of methionine (Met) and cysteine (Cys) delays the aging process and aging-related diseases, improves glucose and fat metabolism and reduces oxidative stress in numerous laboratory animal models. Little is known regarding the effects of sulfur amino acid restriction in humans. Thus, our objectives were to determine the impact of feeding diets restricted in Met alone (MetR) or in both Met and Cys (total sulfur amino acids, SAAR) to healthy adults on relevant biomarkers of cardiometabolic disease risk. DESIGN: A controlled feeding study. SETTING AND PARTICIPANTS: We included 20 healthy adults (11 females/9 males) assigned to MetR or SAAR diet groups consisting of three 4-wk feeding periods: Control period; low level restriction period (70% MetR or 50% SAAR); and high level restriction period (90% MetR or 65% SAAR) separated by 3-4-wk washout periods. RESULTS: No adverse effects were associated with either diet and level of restriction and compliance was high in all subjects. SAAR was associated with significant reductions in body weight and plasma levels of total cholesterol, LDL, uric acid, leptin, and insulin, BUN, and IGF-1, and increases in body temperature and plasma FGF-21 after 4 weeks (P<0.05). Fewer changes occurred with MetR including significant reductions in BUN, uric acid and 8-isoprostane and an increase in FGF-21 after 4 weeks (P<0.05). In the 65% SAAR group, plasma Met and Cys levels were significantly reduced by 15% and 13% respectively (P<0.05). CONCLUSION: These results suggest that many of the short-term beneficial effects of SAAR observed in animal models are translatable to humans and support further clinical development of this intervention.

Lesion Border Detection of Skin Cancer Images Using Deep Fully Convolutional Neural Network with Customized Weights.

Deep learning techniques have been widely employed in semantic segmentation problems, especially in medical image analysis, for understanding image patterns. Skin cancer is a life-threatening problem, whereas timely detection can prevent and reduce the mortality rate. The aim is to segment the lesion area from the skin cancer image to help experts in the process of deeply understanding tissues and cancer cells' formation. Thus, we proposed an improved fully convolutional neural network (FCNN) architecture for lesion segmentation in dermoscopic skin cancer images. The FCNN network consists of multiple feature extraction layers forming a deep framework to obtain a larger vision for generating pixel labels. The novelty of the network lies in the way layers are stacked and the generation of customized weights in each convolutional layer to produce a full resolution feature map. The proposed model was compared with the top four winners of the International Skin Imaging Collaboration (ISIC) challenge using evaluation metrics such as accuracy, Jaccard index, and dice co-efficient. It outperformed the given state-of-the-art methods with higher values of the accuracy and Jaccard index.

Follow-up of colorectal cancer and patterns of recurrence.

Colorectal cancer is one of the commonest cancers detected as also amongst the most common causes of cancer death. Survival has improved due to better disease understanding and treatment; however, a substantial proportion of patients recur after curative intent therapy. In this article, we will discuss the imaging features of recurrent colorectal cancer and the role of the radiologist in its management.

A prospective longitudinal study to evaluate bone health, implication of FRAX tool and impact on quality of life (FACT-P) in advanced prostate cancer patients.

BACKGROUND: Androgen-deprivation therapy (ADT) as a treatment modality in advanced prostate cancer has deleterious effect on bone mineral density (BMD) and quality of life (QOL). Using FRAX (Fracture Risk Assessment) model, candidates at high risk of fractures can be predicted and appropriate treatment can be initiated at early step to prevent skeletal-related events. Objectives of the present study were to evaluate bone health, implication of FRAX tool in advanced prostate cancer and to see the impact of ADT and Bone-directed therapy (BDT) on FRAX and FACT-P QOL scores. MATERIAL & METHOD: We conducted a prospective longitudinal study of 83 localized and metastatic prostate cancer patients from March 2017 to Dec 2020. FRAX tool using BMD femoral neck (GE-Lunar) was used to compute the probability of 10-year Major osteoporotic fracture (MOF) and hip fracture risk %. Patients who received monthly Zolendronic acid with or without Vitamin-D/calcium supplementation were classified as BDT group. FRAX and FACT-P were measured at baseline and 12 months follow-up and compared between different therapeutic modalities to see the impact on clinical outcomes. RESULTS: Majority of patients had skeletal metastasis (78.3%) and high-grade disease at presentation. Secondary osteoporosis was the most commonly (82.05%) observed clinical risk factor (CRF) followed by smoking (19.23%). Hip fracture risk ≥3% accounted for larger proportion of patients than did MOF risk ≥20% (21.2% and 2.5%, respectively). Statistically significant reduction was observed in both MOF and hip fracture risk in BDT group, while worsening on ADT. ADT duration correlated positively with both MOF and hip fracture risk (R2=0.148, P<0.001 and R2=0.164, P<0.001, respectively). FRAX score accurately predict future fracture events in majority (80%) of high-risk patients. Statistically and clinically significant worsening in PWB, EWB, PCS, FACT-P Total, FACT-P TOI and FAPSI scores were observed in patients on ADT. Statistically and clinically significant improvement was noted in physical well-being in BDT group. However, other QOL domains and FACT-P total scores remained stable. CONCLUSIONS: ADT caused duration depended worsening of FRAX and FACT-P score in these patients while improvements of FRAX were seen on BDT. FRAX tool is advantageous in identifying the patients who require early intervention or therapy to decrease skeletal-related events.

Direct visualization and correlation of liver stereotactic body radiation therapy treatment delivery accuracy with interfractional motion.

This study used the visualization of hypo-intense regions on liver-specific MRI to directly quantify stereotactic body radiation therapy (SBRT) spatial delivery accuracy. Additionally, the interfractional motion of the liver region was determined and compared with the MRI-based evaluation of liver SBRT spatial treatment delivery accuracy. Primovist® -enhanced MRI scans were acquired from 17 patients, 8-12 weeks following the completion of liver SBRT treatment. Direct visualization of radiation-induced focal liver reaction in the form of hypo-intensity was determined. The auto-delineation approach was used to localize these regions, and center-of-mass (COM) discrepancy was quantified between the MRI hypo-intensity and the CT-based treatment plan. To assess the interfractional motion of the liver region, a planning CT was registered to a Cone Beam CT obtained before each treatment fraction. The interfractional motion assessed from this approach was then compared against the localized hypo-intense MRI regions. The mean ± SD COM discrepancy was 1.4 ± 1.3 mm in the left-right direction, 2.6 ± 1.8 mm in an anteroposterior direction, and 1.9 ± 2.6 mm in the craniocaudal direction. A high correlation was observed between interfractional motion of visualized hypo-intensity and interfractional motion of planning treatment volume (PTV); the quantified Pearson correlation coefficient was 0.96. The lack of correlation was observed between Primovist® MRI-based spatial accuracy and interfractional motion of the liver, where Pearson correlation coefficients ranged from -0.01 to -0.26. The highest random and systematic errors quantified from interfractional motion were in the craniocaudal direction. This work demonstrates a novel framework for the direct evaluation of liver SBRT spatial delivery accuracy.

Diagnostic Relevance of GATA 3 Expression in Urinary Bladder Carcinoma of Divergent Differentiation and Other Histological Variants.

GATA binding protein 3, a zinc finger transcription factor, has now been demonstrated as a valuable and sensitive marker for conventional urothelial carcinoma with sparse literature related to its expression in various histological variants. It is a prospective study where 74 consecutive cases of bladder carcinoma were included between August 2016 and January 2017 followed by immunohistochemistry to assess GATA 3 expression in conventional as well as different urothelial carcinoma (UC) variants. Overall, 57 of the 74 lesions (77%) demonstrated nuclear staining for GATA 3. GATA 3 expression significantly correlated with histological grade (P < 0.001) and muscle invasion (P = 0.005). Divergent differentiation was observed in 54% (40/74) of the total cases. The study included 12 different variants of urothelial carcinoma. All or majority of the cases of clear cell (6/6, 100%), glandular (6/8, 75%), and sarcomatoid (4/6, 66.7%) variants expressed GATA 3 in a moderate to strong fashion and belonged to group III or IV. Nested variant, small cell carcinoma, pure squamous cell carcinoma, and squamous component of urothelial carcinoma with squamous differentiation do not show any GATA 3 expression. GATA 3 was expressed more intensely as well as in greater number of tumor cells at lymph node metastatic tumor deposits as compared to the primary tumor. GATA 3 expression was not significantly associated with tumor stage or patients' clinical outcomes. GATA 3 is expressed in majority of variants of UC albeit with variable staining; however, situation is challenging in some variants known to be associated with poor prognosis like nested variant, small cell carcinoma, and squamous cell carcinoma where it is not expressed. Hence, the sensitivity of this determinant is diminished in these variants, which may affect the interpretation of GATA 3 stains at metastatic sites as well as their distinction from secondary bladder involvement, by tumors of non-urothelial origin.

The impact of ultrasound in an integrated one-stop sarcoma clinic.

AIM: To evaluate the utilisation of ultrasound within a one-stop clinic model in a regional bone and soft-tissue sarcoma centre in the UK, assess its contribution to patient management, and compare diagnostic outcomes to general musculoskeletal "lumps and bumps" clinics. MATERIALS AND METHODS: This study was a retrospective evaluation of 1,918 referrals between October 2016 and September 2018. All ultrasound examinations and biopsies were performed by one of two musculoskeletal sarcoma radiologists. Ultrasound criteria for suspicion of malignancy were agreed. Study parameters included patient demographics, imaging modality, imaging findings, biopsy results, and time intervals. Correlation has been made between imaging findings and biopsy results. RESULTS: Five hundred and twenty-four patients (27%) underwent diagnostic ultrasound within the one-stop clinic, out of which 244 (46.5%) underwent an ultrasound-guided biopsy within the same appointment. From this cohort, 412 (78.6%) were given a likely benign diagnosis, either based on imaging alone or in combination with an ultrasound-guided biopsy and a histologically malignant diagnosis was made in the remaining 112 (21.4%). Diagnostic ultrasound within the one-stop sarcoma clinic has a positive predictive value of 86%, negative predictive value of 97%, and sensitivity of 89%. CONCLUSION: Integration of ultrasound within a one-stop sarcoma clinic provides rapid diagnostic imaging input within the outpatient setting and facilitates early effective triaging of patients into appropriate management plans. It reduces waiting times, unnecessary outpatient appointments and short-term patient anxiety. Clinical and communications skills of the sarcoma radiologist are of paramount importance to improving overall efficiency and patient experience.

Meeting report from the joint IARC-NCI international cancer seminar series: a focus on colorectal cancer.

Despite significant progress in our understanding of the etiology, biology and genetics of colorectal cancer, as well as important clinical advances, it remains the third most frequently diagnosed cancer worldwide and is the second leading cause of cancer death. Based on demographic projections, the global burden of colorectal cancer would be expected to rise by 72% from 1.8 million new cases in 2018 to over 3 million in 2040 with substantial increases anticipated in low- and middle-income countries. In this meeting report, we summarize the content of a joint workshop led by the National Cancer Institute and the International Agency for Research on Cancer, which was held to summarize the important achievements that have been made in our understanding of colorectal cancer etiology, genetics, early detection and treatment and to identify key research questions that remain to be addressed.

Eight-plate epiphysiodesis: are we creating an intra-articular deformity?

Aims: Guided growth using eight-plates is commonly used for correction of angular limb deformities in growing children. The principle is of tethering at the physeal periphery while enabling growth in the rest of the physis. The method is also applied for epiphysiodesis to correct limb-length discrepancy (LLD). Concerns have been raised regarding the potential of this method to create an epiphyseal deformity. However, this has not been investigated. The purpose of this study was to detect and quantify the occurrence of deformities in the proximal tibial epiphysis following treatment with eight-plates. Patients and Methods: A retrospective study was performed including 42 children at a mean age of 10.8 years (3.7 to 15.7) undergoing eight-plate insertion in the proximal tibia for correction of coronal plane deformities or LLD between 2007 and 2015. A total of 64 plates were inserted; 48 plates (34 patients) were inserted to correct angular deformities and 16 plates (8 patients) for LLD. Medical records, Picture Archive and Communication System images, and conventional radiographs were reviewed. Measurements included interscrew angle, lateral and medial plateau slope angles measured between the plateau surface and the line between the ends of the physis, and tibial plateau roof angle defined as 180° minus the sum of both plateau angles. Measurements were compared between radiographs performed adjacent to surgery and those at latest follow-up, and between operated and non-operated plateaus. Statistical analysis was performed using BMDP Statistical Software. Results: Slope angle increased in 31 (49.2%) of operated epiphyses by a mean of 5° (1° to 23°) compared with 29 (31.9%) in non-operated epiphyses (p = 0.043). Roof angle decreased in 29 (46.0%) of operated tibias and in 25 (27.5%) of non-operated ones by a mean of 5° (1° to 18°) (p = 0.028). Slope angle change frequency was similar in patients with LLD, varus and valgus correction (p = 0.37) but roof angle changes were slightly more frequent in LLD (p = 0.059) and correlated with the change in inter screw angles (r = 0.74, p = 0.001). Conclusion: The use of eight-plates in the proximal tibia for deformity correction and limb-length equalization causes a change in the bony morphology of the tibial plateau in a significant number of patients and the effect is more pronounced in the correction of LLD. Cite this article: Bone Joint J 2018;100-B:1112-16.

Rates of cannabis use in patients with cancer.

Background: A comprehensive assessment of cannabis use by patients with cancer has not previously been reported. In this study, we aimed to characterize patient perspectives about cannabis and its use. Methods: An anonymous survey about cannabis use was offered to patients 18 years of age and older attending 2 comprehensive and 2 community cancer centres, comprising an entire provincial health care jurisdiction in Canada (ethics id: hreba-17011). Results: Of 3138 surveys distributed, 2040 surveys were returned (65%), with 1987 being sufficiently complete for analysis (response rate: 63%). Of the respondents, 812 (41%) were less than 60 years of age; 45% identified as male, and 55% as female; and 44% had completed college or higher education.Of respondents overall, 43% reported any lifetime cannabis use. That finding was independent of age, sex, education level, and cancer histology. Cannabis was acquired through friends (80%), regulated medical dispensaries (10%), and other means (6%). Of patients with any use, 81% had used dried leaves.Of the 356 patients who reported cannabis use within the 6 months preceding the survey (18% of respondents with sufficiently complete surveys), 36% were new users. Their reasons for use included cancer-related pain (46%), nausea (34%), other cancer symptoms (31%), and non-cancer-related reasons (56%). Conclusions: The survey demonstrated that prior cannabis use was widespread among patients with cancer (43%). One in eight respondents identified at least 1 cancer-related symptom for which they were using cannabis.

Oral supplementation with liposomal glutathione elevates body stores of glutathione and markers of immune function.

BACKGROUND/OBJECTIVES: Glutathione (GSH) is the most abundant endogenous antioxidant and a critical regulator of oxidative stress. Maintenance of optimal tissues for GSH levels may be an important strategy for the prevention of oxidative stress-related diseases. We investigated if oral administration of liposomal GSH is effective at enhancing GSH levels in vivo. SUBJECTS/METHODS: A 1-month pilot clinical study of oral liposomal GSH administration at two doses (500 and 1000 mg of GSH per day) was conducted in healthy adults. GSH levels in whole blood, erythrocytes, plasma and peripheral blood mononuclear cells (PBMCs) were assessed in 12 subjects at the baseline and after 1, 2 and 4 weeks of GSH administration. RESULTS: GSH levels were elevated after 1 week with maximum increases of 40% in whole blood, 25% in erythrocytes, 28% in plasma and 100% in PBMCs occurring after 2 weeks (P<0.05). GSH increases were accompanied by reductions in oxidative stress biomarkers, including decreases of 35% in plasma 8-isoprostane and 20% in oxidized:reduced GSH ratios (P<0.05). Enhancements in immune function markers were observed with liposomal GSH administration including Natural killer (NK) cell cytotoxicity, which was elevated by up to 400% by 2 weeks (P<0.05), and lymphocyte proliferation, which was elevated by up to 60% after 2 weeks (P<0.05). Overall, there were no differences observed between dose groups, but statistical power was limited due to the small sample size in this study. CONCLUSIONS: Collectively, these preliminary findings support the effectiveness of daily liposomal GSH administration at elevating stores of GSH and impacting the immune function and levels of oxidative stress.

Clinical profile of nonsmall cell lung carcinoma patients treated in a single unit at a tertiary cancer care center.

BACKGROUND: Recent advances and understanding in the field of lung cancer and advent of newer treatments have shown a significant improvement in survival in the patients. The present study was conducted to analyze the clinical profile of nonsmall cell lung cancer (NSCLC) patients treated in a single unit at a tertiary cancer care center. MATERIALS AND METHODS: In this retrospective analysis, 322 consecutive NSCLC patients from the year 2011 to 2012 treated in a single unit were included in the study. Patients with proven NSCLC were included in the study. The details of the patients included the demographic profile, pathological diagnosis as well as imaging data, tumor profile, details of treatment, and follow-up information. RESULTS: The majority of the patients (95.6%) were in the age group >40 years. A large group of the patients (57.1%) were present/reformed smokers. The major histological type was adenocarcinoma (60.9%), of which 22.8% patients were found to be epidermal growth factor receptor positive. Anaplastic lymphoma kinase rearrangement positivity rate was 4.8%. Furthermore, 68% patients had Stage 4 disease. Upfront palliative chemotherapy (CT) was offered in 61.8% patients and pemetrexed with platinum compounds was the main CT regimen (46.6%). Partial response was achieved in 45.7% patients, whereas stable disease was observed in 10.9% cases. Median progression-free survival was 5 months and overall survival was 55% at 36 months. CONCLUSION: NSCLC forms the largest subgroup of lung cancer with the patients presenting with advanced stages of disease. This area needs to be explored for the early detection and subsequently the radical treatment of the patients. Personalized approach may be considered for the management of lung cancer by identifying new predictive and prognostic biomarkers of this disease.

Effect of immobilisation on production of rapamycin by Streptomyces hygroscopicus.

Numerous antibiotics as secondary metabolites have been isolated from microbes specifically Streptomyces sp. Rapamycin is one of these, which exhibits many roles as immunosuppressant, antifungal antibiotic, anti-tumour etc. Constant thrust has been put by many researchers to improve the production of rapamycin by Streptomyces hygroscopicus. Past research show that whole cell immobilisation is a useful strategy for antibiotic production with economical advantage. This study is another attempt in this direction which involves immobilisation of producer organism on various supports such as polyutherane foam, sintered beads, glass beads and foam peanuts. These support materials have been selected based on their availability and were pre-treated chemically to improve their adsorption capacity. Comparative profiles have been studied to identify the most suited support for the growth of Streptomyces sp. Variation of biomass immobilisation on various support materials with respect to time in batch culture was studied. Cell release study for the carriers was carried out in production medium to evaluate the performance of beads. Also, scanning electron microscopy (SEM) has been employed for visualisation and analysis of immobilised biomass and measurement of pore size. This study aims to determine a suitable support for immobilisation of Streptomyces hygroscopicus which could be used for rapamycin production in batch and continuous mode.

Comprehensive geriatric assessment in 326 older women with early breast cancer.

BACKGROUND: One-third of new early breast cancer diagnoses occur in women over 70 years old. However, older women are less likely to receive radical curative treatments. This study prospectively evaluated a cohort of older women using a Comprehensive Geriatric Assessment (CGA) to determine whether fitness explained the apparent under-treatment in this patient group. METHODS: In this multi-centre prospective study, patients aged ⩾70 years with Stages I-III breast cancer underwent a pretreatment baseline CGA consisting of eight assessment tools. Patients were defined as 'fit' if they had normal score in seven out of eight of the assessment tools. 'High risk' patients were defined as those with grade 3, ER negative, HER2 positive, or node positive breast cancer. RESULTS: Data on 326 patients were available for full analysis. The median age was 77 years. In all, 182 (56%) of the total population were defined as high risk, with 49%, 61% and 53% of those in the 70-74, 75-84 and ⩾85 years age groups respectively having high risk tumours. A total of 301 patients had sufficient CGA records of whom 131 (44%) were reported as fit, with 34%, 54% and 12% of them in the 70-74, 75-84 and ⩾85 years age groups respectively. More fit than unfit patients underwent primary breast surgery (100% vs 91%, P=0.0002), axillary surgery (92% vs 84%, P=0.0340), and adjuvant chemotherapy for high-risk disease (51% vs 20%, P=0.0001). Rates of adjuvant radiotherapy after wide local excision were not significantly different (88% vs 90% respectively, P=0.8195). CONCLUSIONS: In this study, all women ⩾70 years deemed fit by CGA underwent primary surgery. Nearly 50% of fit women with high-risk disease did not receive adjuvant chemotherapy suggesting under treatment in this group.

Aetiology of preoperative anaemia in patients undergoing elective cardiac surgery-the challenge of pillar one of Patient Blood Management.

Preoperative anaemia is common in patients undergoing cardiac surgery. Whilst there is a strong association with increased morbidity and mortality, it is currently unclear whether treatment of anaemia leads to patient benefit. This retrospective study aimed to determine the aetiology of preoperative anaemia in a cohort of patients undergoing elective cardiac surgery over two years at a tertiary hospital. Laboratory data obtained at the preoperative assessment clinic visit were assessed to stratify patients into four groups-iron deficiency anaemia (IDA), possible IDA, anaemia of chronic disease (ACD) and non-anaemic patients with low ferritin according to the 'Preoperative haemoglobin assessment and optimisation template' of the Australian Patient Blood Management (PBM) Guidelines. Of patients with preoperative anaemia, 23.1% had IDA, 6.6% had possible IDA and 70.3% had possible ACD. Of the patients with possible ACD, 30% had a ferritin <100 µg/l, representing limited iron stores or coexisting absolute iron deficiency in the setting of chronic disease. In addition, 46.2% of those with possible ACD had iron studies indicative of functional iron deficiency. Time between assessment and surgery was as little as one day in a third of patients and in only 7% was it more than seven days. Our findings indicate that about one-third of our patients with preoperative anaemia had evidence of iron deficiency, a potentially reversible cause of anaemia. In addition, a significant number had either limited iron stores that may render them iron deficient by surgery, or a functional iron deficiency.

Fruit and vegetable intake and risk of incident of type 2 diabetes: results from the consortium on health and ageing network of cohorts in Europe and the United States (CHANCES).

BACKGROUND/OBJECTIVES: There is limited information to support definitive recommendations concerning the role of diet in the development of type 2 Diabetes mellitus (T2DM). The results of the latest meta-analyses suggest that an increased consumption of green leafy vegetables may reduce the incidence of diabetes, with either no association or weak associations demonstrated for total fruit and vegetable intake. Few studies have, however, focused on older subjects. SUBJECTS/METHODS: The relationship between T2DM and fruit and vegetable intake was investigated using data from the NIH-AARP study and the EPIC Elderly study. All participants below the age of 50 and/or with a history of cancer, diabetes or coronary heart disease were excluded from the analysis. Multivariate logistic regression analysis was used to calculate the odds ratio of T2DM comparing the highest with the lowest estimated portions of fruit, vegetable, green leafy vegetables and cabbage intake. RESULTS: Comparing people with the highest and lowest estimated portions of fruit, vegetable or green leafy vegetable intake indicated no association with the risk of T2DM. However, although the pooled OR across all studies showed no effect overall, there was significant heterogeneity across cohorts and independent results from the NIH-AARP study showed that fruit and green leafy vegetable intake was associated with a reduced risk of T2DM OR 0.95 (95% CI 0.91,0.99) and OR 0.87 (95% CI 0.87,0.90) respectively. CONCLUSIONS: Fruit and vegetable intake was not shown to be related to incident T2DM in older subjects. Summary analysis also found no associations between green leafy vegetable and cabbage intake and the onset of T2DM. Future dietary pattern studies may shed light on the origin of the heterogeneity across populations.

The evolving clinical management of cerebral metastases.

Concepts in the management of brain metastases are evolving. Until recently, brain metastases have been considered as a homogenous condition, managed with whole brain radiotherapy, surgical resection for large lesions and stereotactic radiosurgery for smaller lesions. Increasingly, specific systemic medical therapies are being used to treat brain metastases based on the primary site of disease. This disease specific management is causing a change in perspective about brain metastases and has led to improved survival for patients with primary disease subtypes amenable to tailored medical therapies. We review the recent literature to present evidence for the use of subtype specific medical therapies, advances in surgical resection techniques and stereotactic radiosurgery as the primary treatment modalities. The decline in use of whole brain radiotherapy as first line treatment is also discussed. Based on the recent literature, we propose a new management algorithm to reflect the progress in available options for tailoring disease specific treatments and support the change in paradigm to consider brain metastases as separate disease states based on the primary site of cancer rather than as a homogenous entity.