Does Bone-targeted Therapy Benefit Patients with Metastatic Renal Cell Carcinoma?

INTRODUCTION: In metastatic renal cell carcinoma (mRCC), the bone is the second most common site of metastasis and is associated with increased morbidity and poorer quality of life. Bone-targeted therapies (BTTs) such as denosumab and zoledronic acid may prevent skeletal-related events (SREs). However, the benefit of BTTs in combination with tyrosine kinase inhibitors (TKIs) remains unclear. METHODS: We performed a retrospective chart review at the Urologic Cancer Centre for Research and Innovation. Patients with mRCC were included if they had bone metastases treated with TKIs between 2010 and 2017. Our primary outcome was overall survival (OS), defined as the time elapsed from clinical diagnosis of mRCC to death, and modelled using the Kaplan–Meier method. Secondary outcomes included the median time to SRE and the analysis of prognostic factors of OS using Cox proportional hazards regression. RESULTS: In total, 230 patients with mRCC were identified; of which, 46 had bone metastases treated with TKIs and were included in the study (TKI-only, n = 37; TKI + BTT, n = 9). In the TKI + BTT cohort, patients received either denosumab (n = 5) or zoledronic acid (n = 4). At the time of analysis, 63% of patients were deceased. We observed an OS trend favouring the TKI + BTT cohort (13.8 months [95% confidence interval {CI}: 12.3–15.2] vs. 29.6 months [95% CI: 7.2–51.9], hazard ratio [HR]: 1.66 (95% CI: 0.62–4.45), P = 0.31). When patients in the TKI + BTT cohort were stratified by type of therapy (denosumab or zoledronic acid), the median time to SRE was similar between the groups (4.2 months [95% CI: 2.28–6.14] vs. 2.2 months [95% CI: not available], P = 0.71]. On univariate or multivariate analysis, it was found that age, gender, comorbidities, International metastatic RCC database consortium (IMDC) prognostic group and pathologic tumour grade were not significant predictors of worse OS. Pathologic stage 3 or 4 was an independent predictor of worse OS (HR: 5.8, 95% CI: 1.41–24.03, P = 0.015). CONCLUSION: BTTs may have a continued role in the era of targeted therapy and immunotherapy. Further prospective data are required to validate our findings.     

Is There Any Role of Arsenic Toxicity in HPV Related Oral Squamous Cell Carcinoma?

Biological Trace Element Research - Arsenic is a potent human carcinogen affecting the rate of cancer deaths worldwide. In India, West Bengal is the worst affected state by arsenic. To our best...     

Are Additional Trace Elements Necessary in Total Parenteral Nutrition for Patients with Esophageal Cancer Receiving Cisplatin-Based Chemotherapy?

It is known that cisplatin induces the excretion of zinc from the urine and thereby reduces its serum concentration. However, the fluctuation of these trace elements during or after cisplatin-based chemotherapy has not been evaluated. To answer this question, we performed a clinical study in esophageal cancer patients undergoing cisplatin-based chemotherapy. Eighteen patients with esophageal cancer who were not able to swallow food or water orally due to complete stenosis of the esophagus were evaluated. The patients were divided into a control group [total parenteral nutrition (TPN) alone for 28?days, ten cases] and an intervention group (TPN with additional trace elements for 28?days, eight cases). The serum concentrations of zinc, iron, copper, manganese, triiodothyronin (T3), and thyroxin (T4), as alternative indicators of iodine, were measured on days?0, 14, and 28 of treatment, and statistically analyzed on day?28. In the control group, the serum concentration of copper was significantly decreased from 135.4 (day?0) to 122.1???g/ml (day?14), and finally to 110.6???g/ml (day?28, p?=?0.015). The concentration of manganese was also significantly decreased from 1.34 (day?0) to 1.17???g/ml (day?14) and finally to 1.20 (day?28, p?=?0.049). The levels of zinc, iron, T3, and T4 were not significantly changed. In the intervention group, the supplementation with trace elements successfully prevented these decreases in their concentrations. TPN with supplementary trace elements is preferable and recommended for patients who are undergoing chemotherapy in order to maintain the patients?? nutrient homeostasis.     

Neurofilament Heavy Polypeptide Regulates the Akt-β-Catenin Pathway in Human Esophageal Squamous Cell Carcinoma

Aerobic glycolysis and mitochondrial dysfunction are common features of aggressive cancer growth. We observed promoter methylation and loss of expression in neurofilament heavy polypeptide (NEFH) in a significant proportion of primary esophageal squamous cell carcinoma (ESCC) samples that were of a high tumor grade and advanced stage. RNA interference-mediated knockdown of NEFH accelerated ESCC cell growth in culture and increased tumorigenicity in vivo, whereas forced expression of NEFH significantly inhibited cell growth and colony formation. Loss of NEFH caused up-regulation of pyruvate kinase-M2 type and down-regulation of pyruvate dehydrogenase, via activation of the Akt/β-catenin pathway, resulting in enhanced aerobic glycolysis and mitochondrial dysfunction. The acceleration of glycolysis and mitochondrial dysfunction in NEFH-knockdown cells was suppressed in the absence of β-catenin expression, and was decreased by the treatment of 2-Deoxyglucose, a glycolytic inhibitor, or API-2, an Akt inhibitor. Loss of NEFH activates the Akt/β-catenin pathway and increases glycolysis and mitochondrial dysfunction. Cancer cells with methylated NEFH can be targeted for destruction with specific inhibitors of deregulated downstream pathways.     

Is There a Lag Globally in Overweight Trends for Children Compared with Adults?

Objective: To determine relative trends in prevalence for overweight for adults compared with children across high‐income countries (Australia, United Kingdom, and United States), middle‐income countries (Brazil and Russia), and low‐income countries (China and Indonesia). Research Methods and Procedures: Extant nationally representative survey data from 1971 to the present are used. Prevalence of overweight for adults ≥18.0 years of age and children 6.0 to 17.9 years of age were used. Absolute and relative annual rates of change in prevalence of overweight in children and adults were the key outcomes. Results: Absolute rates of increase in overweight were higher among adults than among children in all studied countries except Australia. However, relative rates of increase in overweight indicate faster increases in overweight among children in Brazil, China, and the three high‐income countries. As a result, the relative excess of overweight among adults, seen initially in all countries, increased in Indonesia and Russia, but it decreased in Australia, Brazil, China, United Kingdom, and United States. In Brazil, time trends indicate an acceleration in the annual rate of change in overweight for children and a deceleration for adults, whereas in the United States, the increase in overweight shows acceleration for both children and adults. Discussion: In absolute terms, overweight increased faster among children than adults only in Australia; however, the relative gap between children and adults is closing in four additional countries, Brazil, China, the United Kingdom, and the United States.     

Background Coloration of Squamous Epithelium in Esophago-Pharyngeal Squamous Cell Carcinoma: What Causes the Color Change?

Objectives

This study aims to clarify the cause of background coloration in the epithelia between each dilated intra papillary capillary loop in esophago-pharyngeal squamous cell carcinoma.

Design

This is a single center retrospective study including 124 patients with 160 lesions who underwent esophagogastroduodenoscopy in Nagasaki University Hospital from September 2007 to March 2012; a detailed comparison between endoscopic images and pathology was performed. Immunohistological assessment using anti-human hemoglobin antibody (anti-Hb Ab) was performed to verify the presence of hemoglobin (Hb) component in the cancer cells. Real-time polymerase chain reaction (RT-PCR) and in situ hybridization (ISH) on Hb-β mRNA were performed to assess the production of Hb component within the cancer cells.

Results

A strong positivity for anti-Hb Ab was observed in the squamous cell carcinoma area, whereas non-cancerous mucosa showed no immunopositivity for Hb. The concordance rate between anti-Hb Ab immunoreactivity and the presence of BC was as high as 80.9%. The amount of Hb-β mRNA expression was three times higher in cancer tissues compared with the surrounding non-cancerous mucosa. ISH images showed that the expression exclusively occurred in cancer cells, indicating that Hb is probably produced within cancer cells.

Conclusions

The background coloration observed is partly due to an extravascular component of Hb. RT-PCR and ISH analyses indicate that Hb is produced within cancer cells.     

Is There a Role for the Apex in Shoot Geotropism?

Experiments with horizontal etiolated sunflower (Helianthus annuus L.) seedlings supported centrally such that both apical and basal ends are free to react to geostimulus, revealed that the apical end commences curvature 1 to 2 hours earlier than the basal end. The later curvature in the basal region is a consequence of the absence of growth in the initial period rather than merely slower growth. A comparison of zonal growth rates in a vertical and a horizontal seedling confirmed that geostimulus induces a renewal of growth in a region where growth had ceased. Removing the apical half of the hypocotyl showed that the curvature resulting from this growth initiation in the basal region is dependent on attachment to the apical region. Evidence that this dependence is unlikely to be due to energy deficiency is adduced. The prior response of the apical end to geostimulus and the apically dependent later initiation of new growth in the basal region are compatible with the delay inherent in message transport from apex to base and are considered as evidence for apical involvement in the totality of the seedling's georesponse.     

Downregulation of 14-3-3σ Correlates with Multistage Carcinogenesis and Poor Prognosis of Esophageal Squamous Cell Carcinoma

Aims

The asymptomatic nature of early-stage esophageal squamous cell carcinoma (ESCC) results in late presentation and consequent dismal prognosis This study characterized 14-3-3σ protein expression in the multi-stage development of ESCC and determined its correlation with clinical features and prognosis.

Materials and Methods

Western blot was used to examine 14-3-3σ protein expression in normal esophageal epithelium (NEE), low grade intraepithelial neoplasia (LGIN), high grade intraepithelial neoplasia (HGIN), ESCC of TNM I to IV stage and various esophageal epithelial cell lines with different biological behavior. Immunohistochemistry was used to estimate 14-3-3σ protein in 110 biopsy samples of NEE, LGIN or HGIN and in 168 ESCC samples all of whom had follow-up data. Support vector machine (SVM) was used to develop a classifier for prognosis.

Results

14-3-3σ decreased progressively from NEE to LGIN, to HGIN, and to ESCC. Chemoresistant sub-lines of EC9706/PTX and EC9706/CDDP showed high expression of 14-3-3σ protein compared with non-chemoresistant ESCC cell lines and immortalized NEC. Furthermore, the downregulation of 14-3-3σ correlated significantly with histological grade (P = 0.000) and worse prognosis (P = 0.004). Multivariate Cox regression analysis indicated that 14-3-3σ protein (P = 0.016) and T stage (P = 0.000) were independent prognostic factors for ESCC. The SVM ESCC classifier comprising sex, age, T stage, histological grade, lymph node metastasis, clinical stage and 14-3-3σ, distinguished significantly lower- and higher-risk ESCC patients (91.67% vs. 3.62%, P = 0.000).

Conclusions

Downregulation of 14-3-3σ arises early in the development of ESCC and predicts poor survival, suggesting that 14-3-3σ may be a biomarker for early detection of high-risk subjects and diagnosis of ESCC. Our seven-feature SVM classifier for ESCC prognosis may help to inform clinical decisions and tailor individual therapy.     

Basal Cell Carcinoma in Gorlin’s Patients: a Matter of Fibroblasts-Led Protumoral Microenvironment?

Basal cell carcinoma (BCC) is the commonest tumor in human. About 70% sporadic BCCs bear somatic mutations in the PATCHED1 tumor suppressor gene which encodes the receptor for the Sonic Hedgehog morphogen (SHH). PATCHED1 germinal mutations are associated with the dominant Nevoid Basal Cell Carcinoma Syndrome (NBCCS), a major hallmark of which is a high susceptibility to BCCs. Although the vast majority of sporadic BCCs arises exclusively in sun exposed skin areas, 40 to 50% BCCs from NBCCS patients develop in non photo-exposed skin. Since overwhelming evidences indicate that microenvironment may both be modified by- and influence the- epithelial tumor, we hypothesized that NBCCS fibroblasts could contribute to BCCs in NBCCS patients, notably those developing in non photo-exposed skin areas. The functional impact of NBCCS fibroblasts was then assessed in organotypic skin cultures with control keratinocytes. Onset of epidermal differentiation was delayed in the presence of primary NBCCS fibroblasts. Unexpectedly, keratinocyte proliferation was severely reduced and showed high levels of nuclear P53 in both organotypic skin cultures and in fibroblast-led conditioning experiments. However, in spite of increased levels of senescence associated β-galactosidase activity in keratinocytes cultured in the presence of medium conditioned by NBCCS fibroblasts, we failed to observe activation of P16 and P21 and then of bona fide features of senescence. Constitutive extinction of P53 in WT keratinocytes resulted in an invasive phenotype in the presence of NBCCS fibroblasts. Finally, we found that expression of SHH was limited to fibroblasts but was dependent on the presence of keratinocytes. Inhibition of SHH binding resulted in improved epidermal morphogenesis. Altogether, these data suggest that the repertoire of diffusible factors (including SHH) expressed by primary NBCCS fibroblasts generate a stress affecting keratinocytes behavior and epidermal homeostasis. Our findings suggest that defects in dermo/epidermal interactions could contribute to BCC susceptibility in NBCCS patients.     

Insulin Glargine or Neutral Protamine Hagedorn in Patients with Severe Insulin Resistance: is There A Benefit?

ObjectiveTo determine the benefit of neutral protamine Hagedorn (NPH) insulin compared with insulin glargine in a patient with type 2 diabetes mellitus and severe insulin resistance.MethodsWe describe the patient’s clinical findings and treatment course.ResultsA 52-year-old man with a 3-year history of type 2 diabetes mellitus did not achieve adequate glucose control despite escalation of his treatment regimen to insulin glargine, 80 units twice daily; insulin lispro, 60 units before each meal; and metformin. Dietary and lifestyle changes were emphasized and implemented while medication adherence with appropriate insulin technique was reviewed at each visit. Insulin glargine was replaced with the same dosage of NPH insulin. After 3 months, a significant drop in hemoglobin A_1c was noted, from 9.5% to 6.1%, consistent with the improved capillary glucose measurements. The effect was maintained over the following year, without any major hypoglycemic events.ConclusionNPH insulin might be superior to the long-acting analogue insulin glargine in cases of severe insulin resistance, but randomized studies are needed to confirm our finding and clarify the involved mechanisms. (Endocr Pract. 2012;18:e49-e51)     

Is Hemoglobin Level in Patients with Nasopharyngeal Carcinoma Still a Significant Prognostic Factor in the Era of Intensity-Modulated Radiotherapy Technology?

Background

Hemoglobin (Hb) levels are regarded as an important determinant of outcome in a number of cancers treated with radiotherapy. However, for patients treated with intensity modulated radiotherapy (IMRT), information regarding the prognostic value of hemoglobin level is scarce.

Patients and Methods

A total of 650 patients with nasopharyngeal carcinoma (NPC), enrolled between May, 2005, and November, 2012, were included in this study. The prognostic significance of hemoglobin level (anemia or no-anemia) at three different time points was investigated, including before treatment, during treatment and at the last week of treatment. Univariate and multivariate analyses were conducted using the log–rank test and the Cox proportional hazards model, respectively.

Results

The 5-year OS (overall survival) rate of patients who were anemia and no-anemia before treatment were 89.1%, and 80.7% (P = 0.01), respectively. The 5-year DMFS (distant metastasis-free survival) rate of patients who were anemia and no-anemia before treatment were 88.9%, and 78.2% (P = 0.01), respectively. The 5-year OS rate of patients who were anemia and no-anemia during treatment were 91.7% and 83.3% (P = 0.004). According to multivariate analysis, the pre-treatment Hb level predicted a decreased DMFS (P = 0.007, HR = 2.555, 95% CI1.294–5.046). Besides, the mid-treatment Hb level predicted a decreased OS (P = 0.013, HR = 2.333, 95% CI1.199–4.541).

Conclusions

Hemoglobin level is a useful prognostic factor in NPC patients receiving IMRT. It is important to control the level of hemoglobin both before and during chemoradiotherapy.     

Is There a Phylogenetic Signal in Prokaryote Proteins?

Using the sequence information from nine completely sequenced bacterial genomes, we extract 32 protein families that are thought to contain orthologous proteins from each genome. The alignments of these 32 families are used to construct a phylogeny with the neighbor-joining algorithm. This tree has several topological features that are different from the conventional phylogeny, yet it is highly reliable according to its bootstrap values. Upon closer study of the individual families used, it is clear that the strong phylogenetic signal comes from three families, at least two of which are good candidates for horizontal transfer. The tree from the remaining 29 families consists almost entirely of noise at the level of bacterial phylum divisions, indicating that, even with large amounts of data, it may not be possible to reconstruct the prokaryote phylogeny using standard sequence-based methods. Received: 22 November 1998 / Accepted: 17 February 1999     

Delayed-Type Hypersensitivity to Metals of Environmental Burden in Patients with Takotsubo Syndrome – Is There a Clinical Relevance?

ObjectiveTakotsubo syndrome (TS) is a heart condition characterised by a sudden transient left ventricular dysfunction; its pathophysiology is probably associated with elevated levels of catecholamines but the exact mechanism is not known as yet. Literature and clinical experience suggest that TS affects persons with various comorbidities. This pilot work aims to evaluate the frequency of comorbidities with potential pathological immune reactivity, and to evaluate the potential association between TS and hypersensitivity to metals assessed by LTT-MELISA®.ConclusionOur work shows that conditions with pathological immune reactivity occur frequently in TS patients, and our data suggest a possible association between TS and hypersensitivity to metals (mercury in particular) evaluated by LTT-MELISA®. We also suggest that apart from the triggering stress factor, potential existence of other serious conditions should be considered when taking medical history of TS patients.     

Neuronal Death: Is There a Role for Astrocytes?

Astrocytes are ubiquitous in the brain and have multiple functions. It is becoming increasingly clear that they play an important role in monitoring the neuromicroenvironment in CNS and in information processing or signaling in the nervous system in normal conditions and respond to CNS injuries in a gradual and varied way. It is still debated whether such reactions are beneficial or detrimental. It was believed that reactive astrogliosis observed in most neurological disorders may regulate the removal of toxic compounds produced by damaged neurons and support neuronal growth by releasing trophic factors. However it was also suggested that astrocytes contribute to a decline of neurologic function, for example by accumulation and release of excitotoxic aminoacids after ischemia and oxidative stress, formation of epileptogenic scars in response to CNS injury and metabolism of protoxins to potent toxins. In a number of metabolic diseases astrocytes, not neurons, may be the primary target. The astrocyte's role in normal and pathological conditions will be discussed in the light of recent information about their metabolism, receptor distribution and release.     

Feasibility of Elective Nodal Irradiation (ENI) and Involved Field Irradiation (IFI) in Radiotherapy for the Elderly Patients (Aged ≥ 70 Years) with Esophageal Squamous Cell Cancer: A Retrospective Analysis from a Single Institute

PurposeWe conducted a retrospective analysis to assess the feasibility of involved field irradiation (IFI) in elderly patients with esophageal squamous cell cancer (ESCC).ResultsA total of 137 patients were enrolled. Fifty-four patients (39.4%) were allocated to the ENI group and 83 patients (60.6%) to the IFI group, the median doses in the two groups were 60 Gy and 59.4 Gy, respectively. For the entire group, the median survival time (MST) and PFS were 16 months and 12 months, respectively. The median PFS and 3-year PFS rate in the ENI group were 13 months and 20.6%, compared to 11 months and 21.0% in the IFI groups (p = 0.61). The MST and 3-year OS rate in the ENI and IFI groups were 17 months and 26.4% and 15.5 months and 21.7%, respectively (p = 0.25). The rate of grade ≥ 3 acute irradiation esophagitis in the ENI group was significantly higher than that in the IFI group (18.5% vs. 6.0%; p = 0.027). Other grade ≥ 3 treatment-related toxicities did not significantly differ between the two groups.ConclusionsIFI resulted in decreased irradiation toxicities without sacrificing OS in elderly patients with ESCC.     

HLA-C -35kb Expression SNP Is Associated with Differential Control of β-HPV Infection in Squamous Cell Carcinoma Cases and Controls

A single nucleotide polymorphism (SNP) 35 kb upstream of the HLA-C gene is associated with HLA-C expression, and the high expressing genotype (CC) has been associated with HIV-I control. HLA-C is unique among the classical MHC class I molecules for its role in the control of viral infections and recognition of abnormal or missing self. This immunosurveillance is central to the pathogenesis of non-melanoma skin cancer (NMSC), and of squamous cell carcinoma (SCC) in particular. While sun exposure is a major risk factor for these cancers, cutaneous infections with genus β-HPV have been implicated in the development of SCC. We hypothesized that the high expression HLA-C genotype is associated with β-HPV infections. Therefore, we investigated the association between β-HPV serology and the −35 kb SNP (rs9264942) in a population-based case-control study of 510 SCC cases and 608 controls. Among controls, the high expression −35 kb SNP genotype (CC) reduced the likelihood of positive serology for multiple (≥2) β-HPV infections (OR = 0.49, 95% CI: 0.25–0.97), and β-HPV species 2 infection (OR = 0.43, 95% CI: 0.23–0.79). However, no association with β-HPV status was observed among SCC cases. Our findings suggest that underlying immunogenotype plays an important role in differential control of β-HPV in SCC cases and controls.