Choosing between conventional and hypofractionated prostate cancer radiation therapy: Results from a study of shared decision-making

AimTo evaluate patient choice of prostate cancer radiotherapy fractionation, using a decision aid.BackgroundRecent ASTRO guidelines recommend patients with localised prostate cancer be offered moderately hypofractionated radiation therapy after discussing increased acute toxicity and uncertainty of long-term results compared to conventional fractionation.Materials and methodsA decision aid was designed to outline the benefits and potential downsides of conventionally and moderately hypofractionated radiation therapy. The aid incorporated the ASTRO guideline to outline risks and benefits.ResultsIn all, 124 patients with localised prostate cancer were seen from June-December 2018. Median age was 72 (range 50–90), 49.6 % were intermediate risk (50.4 % high risk). All except three patients made a choice using the aid; the three undecided patients were hypofractionated. In all, 33.9 % of patients chose hypofractionation: falling to 25.3 % for patients under 75 years, 24.3 % for patients living within 30 miles of the cancer centre, and 14.3 % for patients with baseline gastrointestinal symptoms. On multivariate analysis, younger age, proximity to the centre, and having baseline gastrointestinal symptoms significantly predicted for choosing conventional fractionation. Insurance status, attending clinician, baseline genitourinary symptoms, work/carer status, ECOG, cancer risk group and driving status did not impact choice. Reasons for choosing conventional fractionation were certainty of long-term results (84 %) and lower acute bowel toxicity (51 %).ConclusionsMost patients declined the convenience of moderate hypofractionation due to potentially increased acute toxicity, and the uncertainty of long-term outcomes. We advocate that no patient should be offered hypofractionation without a thorough discussion of uncertainty and acute toxicity.     

Evaluating the predictive value of quantec rectum tolerance dose suggestions on acute rectal toxicity in prostate carcinoma patients treated with IMRT

AimTo investigate the predictive value of convenience of rectum dosimetry with Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) dose limits, maximum rectum dose (Dmax), total rectal volume (TVrectum), rectal volume included in PTV (VrectumPTV) on Grade 2–3 acute rectal toxicity for utilization in clinical practice.BackgroundNumerous previous data have reported frequent acute proctitis after external-beam RT of prostate cancer. Predicting toxicity limited with dose information is inadequate in clinical practice due to comorbidities and medications used.Materials and MethodSixty-four non-metastatic prostate cancer patients treated with IMRT were enrolled. Patients were treated to a total dose of 70–76 Gy. Rectal dose volume histograms (DVH) of all patients were evaluated retrospectively, and a QUANTEC Score between 0 and 5 was calculated for each patient. The correlation between the rectal DVH data, QUANTEC score, TVrectum, VrectumPTV, rectum Dmax and Grade 2–3 rectal toxicity was investigated.ResultsIn the whole group grade 1, 2 and 3 acute rectal toxicities were 25%, 18.8% and 3.1%, respectively. In the DVH data, rectum doses of all patients were under RTOG dose limits. Statistically significant correlation was found between grade 2–3 rectal toxicity and TVrectum (p = 0,043); however. It was not correlated with QUANTEC score, VrectumPTV and Dmax.ConclusionOur results were not able to show any significant correlation between increasing convenience with QUANTEC limits and lower rectal toxicity. Conclusively, new dosimetric definitions are warranted to predict acute rectal toxicity more accurately in prostate cancer patients during IMRT treatment.     

Surgery versus radiotherapy: Long term outcomes of T1 glottic cancer

AimThe aim of this study was to compare the outcomes, patterns of failure and laryngeal preservation rates in patients with T1N0 glottic cancer treated with surgery or radiotherapy.Materials/methodsRetrospective study of T1N0 glottic cancer patients treated in our institution between January 2007 and December 2017. Histologically proven squamous cell carcinoma patients, treated with upfront cordectomy/partial laryngectomy (S group) or radiotherapy (RT group) were included. Elective treatment of the neck was not permitted. Local failure (LF), disease-free survival (DFS), ultimate disease-free survival (UDFS), laryngectomy-free survival (LFS), disease-specific mortality (DSM) and overall survival (OS) were evaluated.ResultsTwo hundred and one patients were eligible (172 S group, 29 RT group), with a median follow-up of 38.8 months. Overall, 33 (16%) patients had a recurrence, 30 (17%) in the S group and 3 (10%) in the RT group. Local failure was the predominant site of failure (28 S, 2 RT). Overall, of all those that were salvaged, 17 (8%) underwent total laryngectomy (15 S, 2 RT). There was no significant difference in the 5-year cumulative incidence of LF (20.8% S, 8.1% RT, p = 0.138), 5-y LFS (85.0% vs. 91.7%, p = 0.809), 5-y DFS (67.5% vs. 82.1%, p = 0.343), 5-y UDFS (82.5% vs. 90.3%, p = 0.647) and 5-y OS (84.5% vs. 90.3%, p = 0.892). Multivariate analysis showed no correlation between initial treatment and the analyzed outcomes.ConclusionPrimary surgery or radiotherapy were similar first line options, since they do not differ in all outcomes. Patients’ and physician's preferences must be considered when choosing first treatment.     

Synthesis of gold nanoparticles using Crinum macowanii bulb extracts and the application of these materials in blood detections at crime scenes

We here in report the synthesis of gold nanoparticles (AuNPs) using a Crinum macowanii bulb water extract. The as‐synthesized AuNPs were characterized using ultraviolet–visible spectroscopy, Fourier transform infrared spectroscopy, X‐ray diffraction, transmission electron microscopy, and a zeta potential‐sizer. The results showed that the as‐synthesized AuNPs were crystalline and mostly spherical in shape with a small mixture of triangular, tetrahedral, hexagonal, octagonal, and diamond shapes. The as‐synthesized AuNPs together with those synthesized by conventional methods were subsequently used as enhancers for the luminol signal in blood detection. It was noted that the AuNPs synthesized from the Crinum macowanii bulb water extract could enhance the chemiluminescence signal for blood detection by luminol to the same extent as AuNPs prepared by conventional methods. Furthermore, both types of AuNPs served as fluorescence enhancers for blood detection when luminol was replaced with the bulb water extract.     

Reporter mice for isolating and auditing cell type‐specific extracellular vesicles in vivo

Extracellular vesicles (EVs) are abundant, lipid‐enclosed vectors that contain nucleic acids and proteins, they can be secreted from donor cells and freely circulate, and they can be engulfed by recipient cells thus enabling systemic communication between heterotypic cell types. However, genetic tools for labeling, isolating, and auditing cell type‐specific EVs in vivo, without prior in vitro manipulation, are lacking. We have used CRISPR‐Cas9‐mediated genome editing to generate mice bearing a CD63‐emGFP^{loxP/stop/loxP} knock‐in cassette that enables the specific labeling of circulating CD63⁺ vesicles from any cell type when crossed with lineage‐specific Cre recombinase driver mice. As proof‐of‐principle, we have crossed these mice with Cdh5‐Cre^ERT2 mice to generate CD63^emGFP+ vasculature. Using these mice, we show that developing vasculature is marked with emerald GFP (emGFP) following tamoxifen administration to pregnant females. In adult mice, quiescent vasculature and angiogenic vasculature (in tumors) is also marked with emGFP. Moreover, whole plasma‐purified EVs contain a subpopulation of emGFP⁺ vesicles that are derived from the endothelium, co‐express additional EV (e.g., CD9 and CD81) and endothelial cell (e.g., CD105) markers, and they harbor specific miRNAs (e.g., miR‐126, miR‐30c, and miR‐125b). This new mouse strain should be a useful genetic tool for generating cell type‐specific, CD63⁺ EVs that freely circulate in serum and can subsequently be isolated and characterized using standard methodologies.     

Base excision repair but not DNA double‐strand break repair is impaired in aged human adipose‐derived stem cells

The decline in DNA repair capacity contributes to the age‐associated decrease in genome integrity in somatic cells of different species. However, due to the lack of clinical samples and appropriate tools for studying DNA repair, whether and how age‐associated changes in DNA repair result in a loss of genome integrity of human adult stem cells remains incompletely characterized. Here, we isolated 20 eyelid adipose‐derived stem cell (ADSC) lines from healthy individuals (young: 10 donors with ages ranging 17–25 years; old: 10 donors with ages ranging 50–59 years). Using these cell lines, we systematically compared the efficiency of base excision repair (BER) and two DNA double‐strand break (DSB) repair pathways—nonhomologous end joining (NHEJ) and homologous recombination (HR)—between the young and old groups. Surprisingly, we found that the efficiency of BER but not NHEJ or HR is impaired in aged human ADSCs, which is in contrast to previous findings that DSB repair declines with age in human fibroblasts. We also demonstrated that BER efficiency is negatively associated with tail moment, which reflects a loss of genome integrity in human ADSCs. Mechanistic studies indicated that at the protein level XRCC1, but not other BER factors, exhibited age‐associated decline. Overexpression of XRCC1 reversed the decline of BER efficiency and genome integrity, indicating that XRCC1 is a potential therapeutic target for stabilizing genomes in aged ADSCs.     

Intrinsically altered lung‐resident γδT cells control lung melanoma by producing interleukin‐17A in the elderly

Cancer is an age‐associated disease, potentially related to the altered immune system of elderly individuals. However, cancer has gradually decreased incidence in the eldest globally such as the most common lung cancer, the mechanisms of which remain to be elucidated. In this study, it was found that the number of lung‐resident γδT cells was significantly increased with altered gene expression in aged mice (20–24 months) versus young mice (10–16 weeks). Aged lung Vγ4⁺ and Vγ6⁺ γδT cells predominantly produced interleukin‐17A (IL‐17A), resulting in increased levels in the serum and lungs. Moreover, the aged mice exhibited smaller tumors and reduced numbers of tumor foci in the lungs after challenge with intravenous injection of B16/F10 melanoma cells compared with the young mice. Aged lung Vγ4⁺ and Vγ6⁺ γδT cells were highly cytotoxic to B16/F10 melanoma cells with higher expression levels of CD103. The markedly longer survival of the challenged aged mice was dependent on γδT17 cells, since neutralization of IL‐17A or depletion of indicated γδT cells significantly shortened the survival time. Consistently, supplementation of IL‐17A significantly enhanced the survival time of young mice with lung melanoma. Furthermore, the anti‐tumor activity of aged lung γδT17 cells was not affected by alterations in the load and composition of commensal microbiota, as demonstrated through co‐housing of the aged and young mice. Intrinsically altered lung γδT17 cells underlying age‐dependent changes control lung melanoma, which will help to better understand the lung cancer progression in the elderly and the potential use of γδT17 cells in anti‐tumor immunotherapy.     

Acarbose improved survival for Apc+/Min mice

Acarbose blocks the digestion of complex carbohydrates, and the NIA Intervention Testing Program (ITP) found that it improved survival when fed to mice. Yet, we do not know if lifespan extension was caused by its effect on metabolism with regard to the soma or cancer suppression. Cancer caused death for ~80% of ITP mice. The ITP found rapamycin, an inhibitor to the pro‐growth mTORC1 (mechanistic target of rapamycin complex 1) pathway, improved survival and it suppressed tumors in Apc^+/Min mice providing a plausible rationale to ask if acarbose had a similar effect. Apc^+/Min is a mouse model prone to intestinal polyposis and a mimic of familial adenomatous polyposis in people. Polyp‐associated anemia contributed to their death. To address this knowledge gap, we fed two doses of acarbose to Apc^+/Min mice. Acarbose improved median survival at both doses. A cross‐sectional analysis was performed next. At both doses, ACA fed mice exhibited reduced intestinal crypt depth, weight loss despite increased food consumption and reduced postprandial blood glucose and plasma insulin, indicative of improved insulin sensitivity. Dose‐independent and dose‐dependent compensatory liver responses were observed for AMPK and mTORC1 activities, respectively. Only mice fed the high dose diet exhibited reductions in tumor number with higher hematocrits. Because low‐dose acarbose improved lifespan but failed to reduced tumors, its effects seem to be independent of cancer. These data implicate the importance of improved carbohydrate metabolism on survival.     

Prostatic irradiation-induced sexual dysfunction: A review and multidisciplinary guide to management in the radical radiotherapy era (Part II on Urological Management)

Prostate cancer is the most common malignancy in men and the second leading cause of cancer-related death in men. Radiotherapy is a curative option that is administered via external beam radiation, brachytherapy, or in combination. Sexual dysfunction is a common toxicity following radiotherapy, similar to men undergoing radical prostatectomy, but the etiology is different. The pathophysiology of radiation-induced sexual dysfunction is multi-factorial, and the toxicity is a major cause of impaired quality of life among long-term prostate cancer survivors. Management of a patient’s sexual function during and after radiotherapy requires multidisciplinary coordination of care between radiation oncology, urology, psychiatry, pharmacy, and dermatology. This review provides a framework for clinicians to better understand prostatic radiotherapy-induced sexual dysfunction diagnosis, evaluation, and a patient-centered approach to toxicity preventive strategies and management.     

Predicting toxicity for head and neck cancer patients undergoing radiation therapy: an independent and external validation of MDASI-HN based nomogram

AimWe conducted a study to validate the MDASI-HN based nomogram, which is used to predict the acute toxicities in head and neck cancer patients undergoing radiation therapy with or without chemotherapy.BackgroundTolerance to radiation varies from patient to patient and also depends on various other factors like tumor volume, dose of radiation, chemotherapy. Predicting the toxicities allow us to identify potential candidates who are likely to have a higher toxicity and, in addition, evaluates the nomogram when done on an independent group of patients.Materials and MethodsSixty biopsy confirmed head and neck cancer patients undergoing radiation were the subjects of the study. The patients completed patient reported outcome instrument (PRO) MDASI-HN questionnaire at the beginning and at the fifth week of radiation. The baseline score obtained was used to obtain the predicted score using nomogram. The nomogram was also externally validated as per the TRIPOD guidelines.ResultsThe mean baseline, predicted and score at the fifth week were 27.28 ± 11.04, 73.33 ± 15.51 and 82.62 ± 17.67, respectively, for all sub-sites. A positive, significant correlation (p < 0.01) between the predicted score and the score at the fifth week was seen across all sub sites such as Oral cavity (p = 0.05), Oropharynx (p = 0.02), Hypo pharynx (p = 0.02) and Larynx (p = 0.02).ConclusionThe MDASI-HN questionnaire based nomogram is simple, easily doable and takes into consideration the initial symptoms as well the treatment details; thereby, it is able to predict the toxicities accurately.