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Δευτέρα 23 Νοεμβρίου 2020

Impact of prior cancer history on the survival of patients with larynx cancer

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Abstract

Background

Patients with a prior history of cancer are commonly excluded from clinical trial. Increasing number of studies implied that a prior cancer did not adversely affect the clinical outcome among various types of cancer patients. However, the impact of prior cancer on survival of larynx cancer patients remains largely unknown. The aim of this study was to evaluate the prevalence of prior cancer and assess its impact on survival of patients diagnosed with larynx cancer.

Methods

Patients with larynx cancer as the first or second primary malignancy diagnosed from 2004 to 2015 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Propensity score matching (PSM) was conducted to balance baseline characteristics. Kaplan-Meier method, multivariate Cox proportional hazard model, and multivariate competing risk model were performed for survival analysis.

Results

A total of 24,812 eligible patients with larynx cancer were included in the study, wherein a total of 2436 patients (9.8%) had a prior history of cancer. Prostate (36%), lung and bronchus (10%), urinary bladder (7%), and breast (6%) were the most common types of prior cancer. A prior cancer history served as a risk factor for overall survival (AHR =1.30; 95% CI [1.21–1.41]; P < 0.001) but a protective factor for cancer-specific mortality (AHR = 0.83; 95% CI [0.72–0.94]; P = 0.004) in comparison with those without prior cancer. The subgroup analysis showed that a prior history of cancer adversely affected overall survival of patients with larynx cancer in most subgroups stratified by timing and types of prior cancer, as well as by different clinicopathologic features.

Conclusion

Our study indicated an adverse survival impact of a prior history of cancer on patients with larynx cancer. Except for a few particular prior cancer, clinical trials should be considered prudently for laryngeal cancer patients with prior cancers.

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Whole-brain irradiation differentially modifies neurotransmitters levels and receptors in the hypothalamus and the prefrontal cortex

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Abstract

Background

Whole-brain radiotherapy is a primary treatment for brain tumors and brain metastasis, but it also induces long-term undesired effects. Since cognitive impairment can occur, research on the etiology of secondary effects has focused on the hippocampus. Often overlooked, the hypothalamus controls critical homeostatic functions, some of which are also susceptible after whole-brain radiotherapy. Therefore, using whole-brain irradiation (WBI) in a rat model, we measured neurotransmitters and receptors in the hypothalamus. The prefrontal cortex and brainstem were also analyzed since they are highly connected to the hypothalamus and its regulatory processes.

Methods

Male Wistar rats were exposed to WBI with 11 Gy (Biologically Effective Dose = 72 Gy). After 1 month, we evaluated changes in gamma-aminobutyric acid (GABA), glycine, taurine, aspartate, glutamate, and glutamine in the hypothalamus, prefrontal cortex, and brainstem according to an HPLC method. Ratios of Glutamate/GABA and Glutamine/Glutamate were calculated. Through Western Blott analysis, we measured the expression of GABAa and GABAb receptors, and NR1 and NR2A subunits of NMDA receptors. Changes were analyzed comparing results with sham controls using the non-parametric Mann–Whitney U test (p < 0.05).

Results

WBI with 11 Gy induced significantly lower levels of GABA, glycine, taurine, aspartate, and GABAa receptor in the hypothalamus. Also, in the hypothalamus, a higher Glutamate/GABA ratio was found after irradiation. In the prefrontal cortex, WBI induced significant increases of glutamine and glutamate, Glutamine/Glutamate ratio, and increased expression of both GABAa receptor and NMDA receptor NR1 subunit. The brainstem showed no statistically significant changes after irradiation.

Conclusion

Our findings confirm that WBI can affect rat brain regions differently and opens new avenues for study. After 1 month, WBI decreases inhibitory neurotransmitters and receptors in the hypothalamus and, conversely, increases excitatory neurotransmitters and receptors in the prefrontal cortex. Increments in Glutamate/GABA in the hypothalamus and Glutamine/Glutamate in the frontal cortex indicate a neurochemical imbalance. Found changes could be related to several reported radiotherapy secondary effects, suggesting new prospects for therapeutic targets.

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The impact of lifecourse socio-economic position and individual social mobility on breast cancer risk

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Abstract

Background

Women with an advantaged socioeconomic position (SEP) have a higher risk of developing breast cancer (BC). The reasons for this association do not seem to be limited to reproductive factors and remain to be understood. We aimed to investigate the impact of lifecourse SEP from childhood and social mobility on the risk of BC considering a broad set of potential mediators.

Methods

We used a discovery-replication strategy in two European prospective cohorts, E3N (N = 83,436) and EPIC-Italy (N = 20,530). In E3N, 7877 women were diagnosed with BC during a median 24.4 years of follow-up, while in EPIC-Italy, 893 BC cases were diagnosed within 15.1 years. Hazard ratios (HR) were estimated using Cox proportional hazard models on imputed data.

Results

In E3N, women with higher education had a higher risk of BC (HR [95%CI] = 1.21 [1.12, 1.30]). This association was attenuated by adjusting for reproductive factors, in particular age at first childbirth (HR[95%CI] = 1.13 [1.04, 1.22]). Health behaviours, anthropometric variables, and BC screening had a weaker effect on the association. Women who remained in a stable advantaged SEP had a higher risk of BC (HR [95%CI] = 1.24 [1.07; 1.43]) attenuated after adjustment for potential mediators (HR [95%CI] = 1.13 [0.98; 1.31]). These results were replicated in EPIC-Italy.

Conclusions

These results confirm the important role of reproductive factors in the social gradient in BC risk, which does not appear to be fully explained by the large set of potential mediators, including cancer screening, suggesting that further research is needed to identify additional mechanisms.

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High cumulative doxorubicin dose for advanced soft tissue sarcoma

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Abstract

Background

The recommended cumulative doxorubicin dose in soft tissue sarcoma (STS) treatment was based on cardiotoxicity data from retrospective studies of breast cancer patients. However, the treatment and prognosis of STS and breast cancer are quite different, and reference to breast cancer data alone may not reflect the efficacy of doxorubicin treatment in STS. This study, thus, aimed to review and analyze clinical data of STS patients treated with a high cumulative doxorubicin dose, to provide a reference for treatment selection and clinical trial design.

Methods

We retrospectively collected and analyzed clinical data of patients with advanced STS who received doxorubicin-based chemotherapy from January 2016 to January 2020. The patients were divided into a standard-dose group (who received ≤6 cycles of doxorubicin after the initial diagnosis) and an over-dose group (who were re-administered doxorubicin [doxorubicin-rechallenge] after receiving 6 cycles of doxorubicin therapy discontinuously). Patient characteristics, cumulative doxorubicin dose, objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), cardiotoxicity incidence, and treatment effectiveness were evaluated in both groups.

Results

A total of 170 patients with advanced STS were recruited (146 in the standard-dose group and 24 in the over-dose group). The average cumulative doxorubicin dose was 364.04 ± 63.81 mg/m2 in the standard-dose group and 714.38 ± 210.09 mg/m2 in the over-dose group. The ORR, DCR, and median PFS were 15.07, 58.9%, and 6 (95% confidence interval [CI]: 5.8–6.5) months in the standard-dose group and 16.67, 66.67%, and 4 (95%CI: 2.0–5.8) months in the over-dose group, respectively. Symptomatic heart failure occurred in five patients (3.42%) of the standard-dose group and in one patient (4.17%) of the over-dose group. In these patients with cardiotoxicity, doxorubicin was discontinued, and all of them died of uncontrolled tumor growth. No drug-related deaths occurred.

Conclusions

The continuation of or rechallenge with doxorubicin beyond the recommended cumulative dose could be a promising therapeutic option in the treatment of chemotherapy-sensitive advanced sarcomas. Further evaluation is necessary in prospective trials.

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Bladder cancer stage and mortality: urban vs. rural residency

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Abstract

Objective

Relative to urban populations, rural patients may have more limited access to care, which may undermine timely bladder cancer (BCa) diagnosis and even survival.

Methods

We tested the effect of residency status (rural areas [RA < 2500 inhabitants] vs. urban clusters [UC ≥ 2500 inhabitants] vs. urbanized areas [UA, ≥50,000 inhabitants]) on BCa stage at presentation, as well as on cancer-specific mortality (CSM) and other cause mortality (OCM), according to the US Census Bureau definition. Multivariate competing risks regression (CRR) models were fitted after matching of RA or UC with UA in stage-stratified analyses.

Results

Of 222,330 patients, 3496 (1.6%) resided in RA, 25,462 (11.5%) in UC and 193,372 (87%) in UA. Age, tumor stage, radical cystectomy rates or chemotherapy use were comparable between RA, UC and UA (all p > 0.05). At 10 years, RA was associated with highest OCM followed by UC and UA (30.9% vs. 27.7% vs. 25.6%, p < 0.01). Similarly, CSM was also marginally higher in RA or UC vs. UA (20.0% vs. 20.1% vs. 18.8%, p = 0.01). In stage-stratified, fully matched CRR analyses, increased OCM and CSM only applied to stage T1 BCa patients.

Conclusion

We did not observe meaningful differences in access to treatment or stage distribution, according to residency status. However, RA and to a lesser extent UC residency status, were associated with higher OCM and marginally higher CSM in T1N0M0 patients. This observation should be further validated or refuted in additional epidemiological investigations.

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Circ-ZNF124 downregulation inhibits non-small cell lung cancer progression partly by inactivating the Wnt/β-catenin signaling pathway via mediating the miR-498/YES1 axis

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Non-small cell lung cancer (NSCLC) is a major type of lung cancer, leading to a high fatality rate. The role of circular RNAs (circRNAs) in cancer has been increasingly emphasized and studied. However, the function of circ-ZNF124 in NSCLC is largely unclear, and associated regulatory mechanism is not studied. Here, we examined the expression pattern of circ-ZNF124 using quantitative real-time PCR. For functional analysis, cell proliferation, cell apoptosis/cycle and cell invasion were investigated using MTT [3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide] assay, flow cytometry assay and transwell assay, respectively. As results, we found that the expression of circ-ZNF124 was elevated in NSCLC tissues and cells. Functionally, circ-ZNF124 downregulation inhibited NSCLC cell proliferation and invasion but induced apoptosis and cycle arrest in vitro, and blocked tumor growth in vivo by animal experiments. Mechanistically, we identified that miR-498 was a target of circ-ZNF124, and miR-498 directly bound to YES proto-oncogene 1 (YES1). Besides, rescue experiments discovered that the cellular effects caused by circ-ZNF124 downregulation could be reversed by miR-498 inhibition or YES1 overexpression. Moreover, we discovered that circ-ZNF124 downregulation inactivated the expression of β-catenin and c-Myc by mediating the miR-498/YES axis. In conclusion, these findings supported that circ-ZNF124 regulated the expression of YES1 by acting as a sponge of miR-498, thus restraining NSCLC development by inactivating the Wnt/β-catenin signaling pathway, which provided a novel strategy to treat NSCLC. Received 19 January 2020 Revised form accepted 3 October 2020 Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website, www.anti-cancerdrugs.com. Correspondence to Fei Gao, Department of Oncology, The Third Hospital of Mianyang (Sichuan Mental Health Center), No. 190, East Section of Jiannan Road, Sichuan 621000, China, Tel: +86 08162271905; e-mail: ipp7ssf@163.com Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.
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Weekly versus triweekly cisplatin-alone adjuvant chemoradiotherapy after radical hysterectomy for stages IB–IIA cervical cancer with risk of recurrence

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Weekly and triweekly cisplatin-alone concomitant chemoradiotherapy regimens after radical surgery were compared in stages IB–IIA cervical cancer with intermediate- or high-risk factors to identify the better therapeutic regimen. We retrospectively analyzed patients with stages IB–IIA cervical cancer who received radical hysterectomy followed by concurrent adjuvant chemoradiotherapy to compare the efficiency between weekly and triweekly regimen groups. We evaluated between-group differences in survival, recurrence, compliance, and adverse effects. A total of 217 patients were included in this study (triweekly group vs. weekly group; 97 vs. 120). The mean follow-up was 47.2 months. The 5-year disease-free survival (DFS) was 84.4% or 76.5% for patients treated with triweekly c isplatin chemotherapy or the weekly regimen, respectively (P = 0.110). The 5-year overall survival (OS) was 82.4 and 78.6% for the same treatment groups, respectively (P = 0.540). The DFS of the patients with pelvic lymph node metastasis were marginally better in triweekly regimen group compared with the weekly group (P = 0.031). Grades 3–4 leukopenia was significantly more common in the triweekly group (P = 0.028). The weekly cisplatin chemotherapy group experienced the same therapeutic effect as the triweekly cisplatin-alone chemotherapy group but with less toxicity. However, triweekly cisplatin regimen reduced the recurrence in patients with pelvic lymph node metastasis. * Jiahao Zhu, Rui Lou, and Shengjun Ji contributed equally to the writing of this article. Received 15 May 2020 Revised form accepted 14 October 2020 Correspondence to Ke Gu, MD, PhD, Department of Radiation Oncology, Affiliated Hospital of Jiangnan University, 200 Huihe Road, Wuxi, China, 214062, Tel: +86051088682999; fax: +051085808820; e-mail: drguke@163.com Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.
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Κυριακή 22 Νοεμβρίου 2020

EEG Characteristics during Short-Term Spontaneous Waking Periods of Different Durations with Changes in Psychomotor Activity Induced by Falling Asleep

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Changes in EEG spectral characteristics during periods of recovery of performance in a psychomotor test during spontaneous short-term periods of waking in daytime sleep were studied in 17 healthy subjects. The test consisted of two sequentially alternating tasks: to count from 1 to 10 silently accompanied by synchronized pressing of a button, and silent counting only. The monotonous nature of the test led to a rapid decline in the level of consciousness and, in most cases, induced falling asleep. Presses serves as a behavioral indicator of the recovery of cognitive processes inhibited during sleep. Situations with small (2–5) and relatively large (6–10) numbers of button presses were compared. The start of pressing was preceded by the appearance of generalized α rhythm, which decreas ed during performance of psychomotor activity. The power of this rhythm was always greater in longer periods of observed behavioral activity. The end of pressing returned α-power indicators to levels seen before waking. The EEG α rhythm in decreased consciousness during short-term waking evidently characterized the action of the thalamocortical activatory mechanism and was a necessary condition for motor interaction of the body with the external environment. The absence of any differences in the frontal areas at the initial stage on performance of short-lived activity and longer-lasting activity, approaching performance of the complete cycle of presses, suggested that they are involved to the same extent during this period regardless of the number of presses. This result may provide indirect support for the notion that the observed psychomotor activity, even with a small number of presses, is not automatic and unconscious but is accompanied by reduced and fragmented consciousness.

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Cross-Correlation and Coherence Analysis of Electrocortigrams in Rats Subjected to Craniocerebral Trauma

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Craniocerebral trauma (CCT) is one of the leading causes of death and long-term loss of work capacity among the young population of both the Russian Federation and other countries. The development of adequate and reproducible models of CCT in laboratory animals and objective methods for assessing the extent of neurological impairments gives cause for optimism in seeking and studying new and effective neurorehabilitation approaches. The aim of the present work was to carry out a comparative cross-correlation and coherence analysis of electrocorticograms from presumptively healthy rats and animals subjected to CCT. After initial trepanning, open penetrating CCT was modeled by controlled cortical impacts applied to the motor cortex of the left hemisphere. Nichrome corticographic recording el ectrodes were implanted bilaterally in the primary and secondary motor cortex and in the primary somatosensory cortex (above the hippocampus). Electrocorticograms were recorded on days 3 and 7 after surgery in the home cage and in the resting state. Cross-correlation analysis consisted of computing the cross-correlation coefficient, the mean frequency, and the maximum span in the cross-correlation function. Mean coherence power levels for the δ, θ, α, and β rhythms were computed for pairs of leads. Unilateral traumatic damage to the motor cortex and underlying structures led to impairment to the operation of interhemisphere and intrahemisphere connections and these changes were seen not only in the impact area, but also in distant parts of the cortex on post-trauma days 3 and 7. These changes in ECoG cross-correlation and coherence parameters occurring in rats as a result of CCT were similar to those seen in patients in clinical practice, so it can be suggested that this experim ental model can be used for neurophysiological and pharmacological research.

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Absorbed dose simulation of meta - 211 At-astato-benzylguanidine using pharmacokinetics of 131 I-MIBG and a novel dose conversion method, RAP

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Abstract

Objective

We aimed to estimate in vivo 211At-labeled meta-benzylguanidine (211At-MABG) absorbed doses by the two dose conversion methods, using 131I-MIBG biodistribution data from a previously reported neuroblastoma xenograft model. In addition, we examined the effects of different cell lines and time limitations using data from two other works.

Methods

We used the framework of the Monte Carlo method to create 3200 virtual experimental data sets of activity concentrations (kBq/g) to get the statistical information. Time activity concentration curves were produced using the fitting method of a genetic algorithm. The basic method was that absorbed doses of 211At-MABG were calculated based on the medical internal radiation dose formalism with the conversion of the physical half-life time of 131I to that of 211At. We have further improved the basic method; that is, a novel dose conversion method, RAP (Ratio of Pharmacokinetics), using percent injected dose/g.

Results

Virtual experiments showed that 211At-MABG and 131I-MIBG had similar properties of initial activity concentrations and biological components, but the basic method did not simulate the 211At-MABG dose. Simulated 211At-MABG doses from 131I-MIBG using the RAP method were in agreement with those from 211At-MABG, so that their boxes overlapped in the box plots. The RAP method showed applicability to the different cell lines, but it was difficult to predict long-term doses from short-term experimental data.

Conclusions

The present RAP dose conversion method could estimate 211At-MABG absorbed doses from the pharmacokinetics of 131I-MIBG with some limitations. The RAP method would be applicable to a large number of subjects for targeted nuclide therapy.

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Evaluation of different airway tests to determine difficult intubation in apparently normal adult patients: undergoing surgical procedures

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Abstract

Background

Inadequate maintenance of a patient's airway represents a major cause of anesthesia-related morbidity and mortality. This study was designed to evaluate common preoperative clinical tests to determine the risk of difficult endotracheal intubation in apparent "normal" adult patients undergoing surgical procedures.

Methods

A prospective observational cohort study was performed on 160 consecutive adult patients undergoing surgical procedures at an academic medical center in Jordan from 20 May 2019 until 11 February 2020.

Preoperative assessment of airway risk stratification was performed by the following clinical tests: the mandible protrusion test (MPT), thyromental (TMD) and sternomental (SMD) distances, inter-incisor gap (IIG), and the modified Mallampati tests with tongue protrusion (MMT-TP) and without tongue protrusion (MMT-NTP). Grade C on the MPT, TMD ≤ 6 cm, SMD ≤ 12 cm, and MMT grades III and IV were considered to be predictors of difficult endotracheal intubations. A modified Cormack-Lehane grading (MCLG) of laryngoscopic views with backward, upward, and right-sided pressure on the thyroid and cricoid cartilages (BURP) maneuver was also documented, with grades 2B, 3, and 4 considered to be difficult airways for intubation.

Results

Fifteen patients (9.4%) were classified as MCLG 2B, 3, and 4, with age significantly associated with the MCLG grade (P = 0.028). The sensitivity and Youden's index of MMT-TP were found to be the lowest (40% and 0.29, respectively). The MPT was the most accurate and specific test (90.63 and 95.17%, respectively), with the highest PPV (50%), Youden's index (0.42), and area under the curve (AUC) (0.781). Bivariant analysis of MPT and the t-test of the mean TMDs and SMDs revealed significant associations between these airway tests and the difficulty of intubation (P values: < 0.001, 0.02, < 0.01, respectively).

Conclusion

The MPT, with its highest accuracy, specificity, positive predictive value, and good sensitivity may be used as a routine screening test for preoperative prediction of difficult endotracheal intubations.

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