Incidence of radiation-induced hypothyroidism following head and neck irradiation: a single-center analysis

BackgroundThe purpose of this study was to investigate the incidence of primary hypothyroidism (HT), as well as any correlation between dosimetric parameters and thyroid dysfunctions after neck radiotherapy (RT) in head and neck cancer (HNC) patients.Materials and methodsThis study retrospectively reviewed HNC patients who finished neck RT for at least 12 months and who had available back-up treatment information. Eligible patients further received a single thyroid function test (TFT). Dosimetric parameters of the thyroid glands were retrospectively evaluated in order to detect any correlation between dose-volume parameters and primary HT.ResultsWe reviewed 1,102 HNC patients. Accordingly, 64 patients were deemed eligible and were included in this study. The median time interval between RT completion and TFT was 21 months (interquartile range, 14–34 months), while 26 patients (40.6%) were diagnosed with HT. The thyroid volume spared from a dose of 50 Gy (VS50_Gy) was found to be statistically significant and considered an associated factor for developing HT (p = 0.047). Furthermore, there was an observable trend indicating a reduction in the risk of HT when VS50_Gy was more than 5 cm³ (p = 0.052).ConclusionIn our study, VS50_Gy was determined to be a significant predictive parameter of radiation-induced HT.     

Smoking and other health factors in patients with head and neck cancer

BackgroundInformation on smoking and other health factors in head and neck cancer (HNC) patients throughout treatment, follow-up and survivorship is limited. This study explores patterns of multiple health factors during radiotherapy (RT) and naturalistic long-term follow-up in a convenience sample of patients with HNC.MethodsSmoking, alcohol use and depression were measured at baseline, 4 and 12 weeks post RT for a sub-group of 99 patients who participated in a randomised controlled trial and completed long-term follow-up. These factors plus healthy eating, physical activity and fatigue are also reported from the long-term follow-up component. Smoking was measured by self-report and biochemically, whilst all other variables were by self-report. Where variables were assessed at multiple time points logistic mixed effects regression models determined within-person changes over time.ResultsThere were important discrepancies between self-reported (4–7%) and biochemically verified (13–29%) rates of smoking. Rates of smoking and hazardous alcohol intake were significantly increased at follow-up compared to baseline. Depression rates were observed to be higher at end of RT compared to baseline. At long-term follow-up, fatigue was common and co-occurred with suboptimal healthy eating and hazardous alcohol use.ConclusionClinically important levels of smoking and alcohol consumption post RT in this sample suggest possible targets for intervention beyond treatment into long-term follow-up of patients.     

A cost-effective technique for cardiac sparing with deep inspiration-breath hold (DIBH)

Deep inspiration breath hold (DIBH) is an effective technique to reduce cardiac and pulmonary dose during breast radiotherapy (RT). However, as a result of expense and the technical challenges of program implementation, DIBH has not been widely adopted in clinical practice.This report describes a program for DIBH this is relatively inexpensive to implement and has little impact on patient throughput. Multiple redundant mechanisms are incorporated to assure accurate and safe delivery of RT during DIBH. Laser alignment verifies that chest wall excursion is reliably reproduced and maintained during treatment. Chest wall excursion is also monitored independently using an infrared camera trained on a reflective marker on the chest wall. This system automatically triggers “beam off” in the event of movement of the target beyond pre-determined thresholds. Finally, physician review of cine imaging obtained during treatment provides an off-line verification of accurate RT delivery. The approach described herein lowers the investment necessary for implementation of DIBH and may facilitate broader adoption of this valuable technique.     

Theranostic Gold Nanoparticles Modified for Durable Systemic Circulation Effectively and Safely Enhance the Radiation Therapy of Human Sarcoma Cells and Tumors

Radiation therapy (RT) is an integral component of the treatment of many sarcomas and relies on accurate targeting of tumor tissue. Despite conventional treatment planning and RT, local failure rates of 10% to 28% at 5 years have been reported for locally advanced, unresectable sarcomas, due in part to limitations in the cumulative RT dose that may be safely delivered. We describe studies of the potential usefulness of gold nanoparticles modified for durable systemic circulation (through polyethylene glycosylation; hereinafter “P-GNPs”) as adjuvants for RT of sarcomas. In studies of two human sarcoma-derived cell lines, P-GNP in conjunction with RT caused increased unrepaired DNA damage, reflected by approximately 1.61-fold increase in γ-H2AX (histone phosphorylated on Ser¹³⁹) foci density compared with RT alone. The combined RT and P-GNP also led to significantly reduced clonogenic survival of tumor cells, compared to RT alone, with dose-enhancement ratios of 1.08 to 1.16. In mice engrafted with human sarcoma tumor cells, the P-GNP selectively accumulated in the tumor and enabled durable imaging, potentially aiding radiosensitization as well as treatment planning. Mice pretreated with P-GNP before targeted RT of their tumors exhibited significantly improved tumor regression and overall survival, with long-term survival in one third of mice in this treatment group compared to none with RT only. Interestingly, prior RT of sarcoma tumors increased subsequent extravasation and in-tumor deposition of P-GNP. These results together suggest P-GNP may be integrated into the RT of sarcomas, potentially improving target imaging and radiosensitization of tumor while minimizing dose to normal tissues.     

Radiotherapy for Hodgkin's lymphoma: too hard to die?

The treatment of Hodgkin's lymphoma (HL) is associated with significant toxicity. The objective of high quality management is to keep the concept of combined modality, while trying to decrease the radiation dose, to diminish to a great extent the irradiated volume and at the same time to reduce the number of chemotherapy courses, introducing the so-called optimisation. New directives should be followed to obtain more effective treatments of HL. Shorter cycles of chemotherapy and the utilization of modern techniques in radiotherapy (RT) constitute fundamental steps to achieve this objective. Analysis of randomized studies supports the inclusion of reduced-field and dose of RT in the radiotherapeutic treatment options for HL. RT is an integral part of the combined-modality therapy (CMT) of HL.     

Combined aerobic and resistance training and vascular function: effect of aerobic exercise before and after resistance training.

Aerobic exercise training combined with resistance training (RT) might prevent the deterioration of vascular function. However, how aerobic exercise performed before or after a bout of RT affects vascular function is unknown. The present study investigates the effect of aerobic exercise before and after RT on vascular function. Thirty-three young, healthy subjects were randomly assigned to groups that ran before RT (BRT: 4 male, 7 female), ran after RT (ART: 4 male, 7 female), or remained sedentary (SED: 3 male, 8 female). The BRT and ART groups performed RT at 80% of one repetition maximum and ran at 60% of the targeted heart rate twice each week for 8 wk. Both brachial-ankle pulse wave velocity (baPWV) and flow-mediated dilation (FMD) after combined training in the BRT group did not change from baseline. In contrast, baPWV after combined training in the ART group reduced from baseline (from 1,025 +/- 43 to 910 +/- 33 cm/s, P < 0.01). Moreover, brachial artery FMD after combined training in the ART group increased from baseline (from 7.3 +/- 0.8 to 9.6 +/- 0.8%, P < 0.01). Brachial artery diameter, mean blood velocity, and blood flow in the BRT and ART groups after combined training increased from baseline (P < 0.05, P < 0.01, and P < 0.001, respectively). These values returned to the baseline during the detraining period. These values did not change in the SED group. These results suggest that although vascular function is not improved by aerobic exercise before RT, performing aerobic exercise thereafter can prevent the deteriorating of vascular function.     

Functional imaging in radiation therapy planning for head and neck cancer

Functional imaging and its application to radiotherapy (RT) is a rapidly expanding field with new modalities and techniques constantly developing and evolving. As technologies improve, it will be important to pay attention to their implementation. This review describes the main achievements in the field of head and neck cancer (HNC) with particular remarks on the unsolved problems.     

Regulatory role of arginine 204 in the catalytic activity of rat alloantigens ART2a and ART2b

ART2a (RT6.1) and ART2b (RT6.2) are NAD glycohydrolases (NADases) that are linked to T lymphocytes by glycosylphosphatidylinositol anchors. Although both mature proteins possess three conserved regions (I, II, III) that form the NAD-binding site and differ by only ten amino acids, only ART2b is auto-ADP-ribosylated and only ART2a is glycosylated. To investigate the structural basis for these differences, wild-type and mutant ART2a and ART2b were expressed in rat mammary adenocarcinoma (NMU) cells and released with phosphatidylinositol-specific phospholipase C. All mutants were immunoreactive NADases. Arginine 204 (Arg204), NH2-terminal to essential glutamate 209 in Region III, is found in ART2b, but not ART2a. Replacement of Arg204 in ART2b with lysine, tyrosine, or glutamate abolished auto-ADP-ribosylation. Unlike wild-type ART2a, ART2a(Y204R) was auto-ADP-ribosylated. The tryptophan mutant ART2b(R204W) was auto-ADP-ribosylated and exhibited enhanced NADase activity. Incubation with NAD and auto-ADP-ribosylation decreased the NADase activities of wild-type ART2b and ART2b (R204W), whereas activity of ART2b(R204K), which is not auto-modified, was unchanged by NAD. Facilitation of auto-ADP-ribosylation by tryptophan 204 suggests that the hydrophobic amino acid mimics an ADP-ribosylated arginine. Thus, Arg204 in ART2b serves as a regulatory switch whose presence is required for additional auto-ADP-ribosylation and regulation of catalytic activity.     

Simplified Paper Format for Detecting HIV Drug Resistance in Clinical Specimens by Oligonucleotide Ligation

Human immunodeficiency virus (HIV) is a chronic infection that can be managed by antiretroviral treatment (ART). However, periods of suboptimal viral suppression during lifelong ART can select for HIV drug resistant (DR) variants. Transmission of drug resistant virus can lessen or abrogate ART efficacy. Therefore, testing of individuals for drug resistance prior to initiation of treatment is recommended to ensure effective ART. Sensitive and inexpensive HIV genotyping methods are needed in low-resource settings where most HIV infections occur. The oligonucleotide ligation assay (OLA) is a sensitive point mutation assay for detection of drug resistance mutations in HIV pol. The current OLA involves four main steps from sample to analysis: (1) lysis and/or nucleic acid extraction, (2) amplification of HIV RNA or DNA, (3) ligation of oligonucleotide probes designed to detect single nucleotide mutations that confer HIV drug resistance, and (4) analysis via oligonucleotide surface capture, denaturation, and detection (CDD). The relative complexity of these steps has limited its adoption in resource-limited laboratories. Here we describe a simplification of the 2.5-hour plate-format CDD to a 45-minute paper-format CDD that eliminates the need for a plate reader. Analysis of mutations at four HIV-1 DR codons (K103N, Y181C, M184V, and G190A) in 26 blood specimens showed a strong correlation of the ratios of mutant signal to total signal between the paper CDD and the plate CDD. The assay described makes the OLA easier to perform in low resource laboratories.     

The role of testosterone in aggressive and non-aggressive risk-taking in adolescent boys

While there exists increasing evidence of a relationship between testosterone (T) and risk-taking (RT), many issues remain unsolved. This paper tries to address two main-questions: (i) does T influence aggressive risk-taking (ART) and/or non-aggressive risk-taking (NART) behavior and (ii) is this relationship stable throughout age and pubertal development and how is the relationship affected by affiliations with peers that are highly involved in RT, referred to as differential association (DA)? For a sample of 301 third-grade adolescent boys (mean age 14.4 years), we assessed the relationship between serum levels of T and estradiol (E2), DA and ART/NART. Significant effects of SHBG (Beta=-0.15; p<0.029) and free testosterone (FT) (Beta=0.23; p<0.003) on NART were shown. No significant effects were found with respect to ART. Further analyses showed that the FT-NART and the FT-ART relations differed as to age but not as to pubertal development (PD) and that the relationship between FT and RT is mediated by DA as such that individuals with higher levels of FT have friends that are more involved in RT and their influence contributes to increased levels of RT. Our results indicate that hormone-related interests and predispositions may influence the development of affiliations with risk-taking peers, a factor which is crucial in understanding adolescent RT.     

Tumor Necrosis Factor Inhibition and Head and Neck Cancer Recurrence and Death in Rheumatoid Arthritis

The objective of this retrospective cohort study was to determine the effect of tumor necrosis factor inhibitor (TNFi) therapy on the risk of head and neck cancer (HNC) recurrence or HNC-attributable death in patients with rheumatoid arthritis (RA). RA patients with HNC were assembled from the US national Veterans’ Affairs (VA) administrative databases, and diagnoses confirmed and data collected by electronic medical record review. The cohort was divided into those treated with non-biologic disease-modifying anti-rheumatic drugs (nbDMARDs) versus TNF inhibitors (TNFi) after a diagnosis of HNC. Likelihood of a composite endpoint of recurrence or HNC-attributable death was determined by Cox proportional hazards regression. Of 180 patients with RA and HNC, 31 were treated with TNFi and 149 with nbDMARDs after the diagnosis of HNC. Recurrence or HNC-attributable death occurred in 5/31 (16.1%) patients in the TNFi group and 44/149 (29.5%) patients in the nbDMARD group (p = 0.17); it occurred in 2/16 (13%) patients who received TNFi in the year prior to HNC diagnosis but not after. Overall stage at diagnosis (p = 0.03) and stage 4 HNC (HR 2.49 [CI 1.06–5.89]; p = 0.04) were risk factors for recurrence or HNC-attributable death; treatment with radiation or surgery was associated with a lower risk (HR 0.35 [CI 0.17–0.74]; p = 0.01 and HR 0.39 [CI 0.20–0.76]; p = 0.01 respectively). Treatment with TNFi was not a risk factor for recurrence or HNC-attributable death (HR 0.75; CI 0.31–1.85; p = 0.54). We conclude that treatment with TNFi may be safe in patients with RA and HNC, especially as the time interval between HNC treatment and non-recurrence increases. In this study, TNF inhibition was not associated with an increase in recurrence or HNC-attributable death.     

Techniques for adaptive prostate radiotherapy

Variations in the position and shape of the prostate make accurate setup and treatment challenging. Adaptive radiation therapy (ART) techniques seek to alter the treatment plan, at one or more points throughout the treatment course, in response to changes in patient anatomy observed between planning and pre-treatment images. This article reviews existing and developing ART techniques for prostate cancer along with an overview of supporting in-room imaging technologies. Challenges to the clinical implementation of adaptive radiotherapy are also discussed.     

Purification to homogeneity of latent and active 58-kilodalton forms of human neutrophil collagenase

Latent and active 58-kDa forms of human neutrophil collagenase (HNC) have been purified to homogeneity. Buffy coats were extracted in the presence and absence of phenylmethanesulfonyl fluoride to generate crude starting preparations that contained latent and active HNC, respectively. The buffers used in preparing these extracts and for all subsequent chromatographic steps contained NaCl at a concentration of 0.5 M or greater, 0.05% Brij-35, concentrations of CaCl2 of 5 mM or greater, and (when feasible) 50 microM ZnSO4 to stabilize the HNC. The collagenase activity in the buffy coat extracts was adsorbed to a Reactive Red 120-agarose column at pH 7.5 in 0.5 M NaCl and was eluted when the NaCl concentration was increased to 1 M. The active and p-(chloromercuri)benzoate-activated latent enzymes were next adsorbed to a Sepharose-CH-Pro-Leu-Gly-NHOH affinity resin in 1 M NaCl at pH 7.5 and desorbed at pH 9 to give a fraction containing only HNC and a small amount of neutrophil gelatinase. The latter enzyme was removed by passage over a gelatin-Sepharose column in 1 M NaCl at pH 7.5. The purified samples of active and latent HNC were obtained with typical cumulative yields of 32 and 82% and specific activities toward soluble rat type I collagen at 30 degrees C of 7200 and 12,000 micrograms min-1 mg-1, respectively. These specific activities are markedly higher than previously reported for HNC. Both active and latent HNC exhibit a single band on sodium dodecyl sulfate-polyacrylamide gel electrophoresis both in the presence and in the absence of 2-mercaptoethanol. The mobility of latent HNC is consistent with a molecular weight of approximately 58K, with the active form exhibiting a slightly lower (less than 1-2K) molecular weight.     

Long-term adherence to antiretroviral treatment and program drop-out in a high-risk urban setting in sub-Saharan Africa: a prospective cohort study

Background

Seventy percent of urban populations in sub-Saharan Africa live in slums. Sustaining HIV patients in these high-risk and highly mobile settings is a major future challenge. This study seeks to assess program retention and to find determinants for low adherence to antiretroviral treatment (ART) and drop-out from an established HIV/ART program in Kibera, Nairobi, one of Africa''s largest informal urban settlements.

Methods and Findings

A prospective open cohort study of 800 patients was performed at the African Medical Research Foundation (AMREF) clinic in the Kibera slum. Adherence to ART and drop-out from the ART program were independent outcomes. Two different adherence measures were used: (1) “dose adherence” (the proportion of a prescribed dose taken over the past 4 days) and (2) “adherence index” (based on three adherence questions covering dosing, timing and special instructions). Drop-out from the program was calculated based on clinic appointment dates and number of prescribed doses, and a patient was defined as being lost to follow-up if over 90 days had expired since the last prescribed dose. More than one third of patients were non-adherent when all three aspects of adherence – dosing, timing and special instructions – were taken into account. Multivariate logistic regression revealed that not disclosing HIV status, having a low level of education, living below the poverty limit (US$ 2/day) and not having a treatment buddy were significant predictors for non-adherence. Additionally, one quarter of patients dropped out for more than 90 days after the last prescribed ART dose. Not having a treatment buddy was associated with increased risk for drop-out (hazard ratio 1.4, 95% CI = 1.0–1.9).

Conclusion

These findings point to the dilemma of trying to sustain a growing number of people on life-long ART in conditions where prevailing stigma, poverty and food shortages threatens the long-term success of HIV treatment.     

HSPA5 negatively regulates lysosomal activity through ubiquitination of MUL1 in head and neck cancer

HSPA5/GRP78/BiP plays an important role in cell survival or tumor progression. For these reasons, HSPA5 is an emerging therapeutic target in cancer development. Here we report that HSPA5 contributes to head and neck cancer (HNC) survival via maintenance of lysosomal activity; however, a nonthermal plasma (NTP, considered as a next-generation cancer therapy)-treated solution (NTS) inhibits HNC progression through HSPA5-dependent alteration of lysosomal activity. HSPA5 prevents NTS-induced lysosome inhibition through lysosomal-related proteins or regulation of gene expression. However, NTS-induced MUL1/MULAN/GIDE/MAPL (mitochondrial ubiquitin ligase activator of NFKB 1) leads to downregulation of HSPA5 via K48-linked ubiquitination at the lysine 446 (K446) residue. MUL1 knockdown hinders NTS-induced lysosome inhibition or cytotoxicity through the reduction of HSPA5 ubiquitination in HNC cells. While MUL1 was suppressed, HSPA5 was overexpressed in tissues of HNC patients. NTS strongly inhibited HNC progression via alterations of expression of MUL1 and HSPA5, in vivo in a xenograft model. However, NTS did not induce inhibition of tumor progression or HSPA5 reduction in MUL1 knockout (KO) HNC cells which were generated by CRISPR/Cas9 system. The data provide compelling evidence to support the idea that the regulation of the MUL1-HSPA5 axis can be a novel strategy for the treatment of HNC.