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Objectives: We aimed to summarize the most significant and impactful publications describing the pharmacotherapeutic care of critically ill patients in 2023., Data Sources: PubMed/MEDLINE and the Clinical Pharmacy and Pharmacology Pharmacotherapy Literature Update., Study Selection: Randomized controlled trials and prospective studies of adult critically ill patients assessing a pharmacotherapeutic intervention and reporting clinical endpoints published between January 1, 2023, and December 31, 2023, were eligible for inclusion in this article., Data Extraction: Articles from a systematic search and the Clinical Pharmacy and Pharmacology Pharmacotherapy Literature Update were included. An a priori defined three-round modified Delphi process was employed to achieve consensus on the most impactful publications based on the following considerations: 1) overall contribution to scientific knowledge and 2) novelty to the literature., Data Synthesis: The systematic search and Clinical Pharmacy and Pharmacology Pharmacotherapy Literature Update returned a total of 1202 articles, of which 1164 were excluded. The remaining 38 articles underwent a three-round modified Delphi process. In each round, articles were independently scored based on overall contribution to scientific knowledge and novelty to the literature. Included articles are summarized and their impact discussed. Article topics included hydrocortisone for severe community-acquired pneumonia, inhaled amikacin for prevention of ventilator-associated pneumonia, methylene blue for septic shock, restrictive vs. liberal fluid management for sepsis-induced hypotension, andexanet alfa for major bleeding associated with factor Xa inhibitors, and early administration of four-factor prothrombin complex concentrate in patients with trauma at risk for massive transfusion., Conclusions: This review provides a summary and perspective on the potential impact of the most relevant articles in 2023 describing advances in the pharmacotherapeutic care of critically ill patients., Competing Interests: Dr. Makic is an editor of critical care texts for Elsevier and chair of clinical practice alerts. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

The purpose of this article is to summarize pharmacotherapy related emergency medicine (EM) literature indexed in 2023. Articles were selected utilizing a modified Delphi approach. The table of contents from pre-determined journals were reviewed and independently evaluated via the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system by paired authors. Pharmacotherapy-related publications deemed to be GRADE 1A and 1B were reviewed by the collective group for inclusion in the review. In all, this article summarizes and provides commentary on the potential clinical impact of 13 articles, 6 guidelines, and 5 meta-analyses covering topics including guideline releases and updates on rapid sequence intubation in the critically ill, managing cardiac arrest or life-threatening toxicity due to poisoning, and management of major bleeding following trauma. Also discussed are ongoing controversies surrounding fluid resuscitation, time and treatment modalities for ischemic stroke, steroid use in community-acquired pneumonia, targeted blood product administration, and much more., Competing Interests: Declaration of competing interest There are two authors who declare potential competing interests. Caitlin Brown has receiving funding from Alexion/Astra Zeneca and Brian Gilbert consults and has received speakers fees from Haemonetics. All other authors have nothing to disclose relevant to this article., (Copyright © 2024. Published by Elsevier Inc.)

With ageing of the population worldwide and discovery of new medications for prevention and management of age-related conditions, there is increasing use of medications by older adults. There are international efforts to increase the representativeness of participants in clinical trials to match the intended real-world users of the medications across a range of characteristics including age, multimorbidity, polypharmacy and frailty. Currently, much of the data on medication-related harm in older adults are from pharmacovigilance studies. New methods in pre-clinical models have allowed for measurement of exposures (such as chronic exposure, polypharmacy and deprescribing) and outcomes (such as health span functional measures and frailty) that are highly relevant to geriatric pharmacotherapy. Here we describe opportunities for design and implementation of pre-clinical models that can better predict drug effects in geriatric patients. This could improve the translation of new drugs from bench to bedside and improve outcomes of pharmacotherapy in older adults., (© 2024. The Author(s).)

Background: The review of pharmacotherapy can be conceptualized as a service in which the drugs used by the patient are reviewed to control the risks as well as to improve the results of the drug therapy, detecting, solving, and preventing issues associated with the drug, readjusting the doses and times (schedule) so that the treatment is not incompatible or in duplicity., Methods: The aim of the study was to validate an intelligent information system, which was developed to assist the scheduling activity in the pharmacotherapy review. The system used the concept of Genetic Algorithms. To validate the system, hypothetical cases were elaborated considering various aspects of pharmacotherapy such as underdose, overdose, drug interactions and contraindications. These cases were tested in the system and were also analyzed by pharmaceutical experts with clinical and research experience in the pharmacotherapy review process. The degree of agreement between the assessments of the appointments carried out by the pharmaceutical specialists and by the system were measured using the Kappa index with a 95% confidence interval., Results: In detecting errors and make propositions, the system was able to identify 80% of errors, with pharmaceutical experts identifying between 20 and 70% of errors. In relation the results of kappa between the cases, the system had 87,3% of concordance, whereas the best pharmaceutical expert had 75,5% of concordance, considering the correct answer., Conclusion: It can be concluded that with the methodology used, the investigation met the objectives and confirmed the system is effective for pharmaceutical review process. There are indications that the system can help in the Pharmacotherapy review process, being able to find prescription errors as well as to establish times for the use of medications according to the patient's routine., (© 2022. The Author(s).)

Cancer cells rely on glycolysis to support a high proliferation rate. Metformin (Met) is a promising drug for tumor treatment that targets hexokinase 2 (HK2) to block the glycolytic process, thereby further disrupting the metabolism of cancer cells. Herein, an intelligent nanomedicine based on glucose deprivation and glycolysis inhibition is creatively constructed for enhanced cancer synergistic treatment. In brief, Met and glucose oxidase (GOx) was encapsulated into histidine/zeolitic imidazolate framework-8 (His/ZIF-8), which was followed by coating with Arg-Gly-Asp (RGD) peptides to obtain the desired nanomedicine (Met/GOx@His/ZIF-8∼RGD). This smart nanomedicine presents the controllable Met and GOx release behavior in an acidic responsive manner. The liberated Met blocks the glycolysis process via suppressing the activity of HK2 and impairing ATP production, which activates the AMP-activated protein kinase (AMPK) pathway and p53 pathway and damages the Warburg effect, eventually leading to cells apoptosis. And the GOx boosts the glucose shortage for starvation therapy by depleting accumulated glucose. According to in vitro and in vivo assays, the combination of glycolysis inhibition and starvation therapy demonstrates efficient cancer cells growth suppression and superior antitumor properties compared to the Met based or GOx-mediated monotherapy. This work provides an advanced therapeutic strategy via disrupting cellular metabolism against cancer. STATEMENT OF SIGNIFICANCE: The obtained nanomedicine (Met/GOx@His/ZIF-8∼RGD) presents the controllable Met and glucose oxidase (GOx) release behavior in an acidic responsive manner. The liberated Met blocks the glycolysis process via suppressing the activity of HK2 and impairing ATP production, which activates the AMP-activated protein kinase (AMPK) pathway and p53 pathway and damages the Warburg effect, eventually leading to cells apoptosis. And the GOx boosts the glucose shortage for starvation therapy by depleting accumulated glucose. The combination of glycolysis inhibition and starvation therapy demonstrate the efficient suppression of cancer cells growth and the superior antitumor properties when compared to the Met based or GOx-mediated monotherapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Anti‑programmed death‑1 (PD‑1)/programmed death‑ligand 1 (PD‑L1)‑directed immunotherapy has revolutionized the treatment of advanced non‑small cell lung cancer (NSCLC). However, predictive biomarkers are still lacking, particularly in identifying PD‑L1 low/negative patients who will benefit from immunotherapy. It was previously reported that farnesoid X receptor (FXR) downregulated PD‑L1 expression in NSCLC, and that FXR high PD‑L1 low mouse Lewis lung carcinoma tumors showed an increased susceptibility to PD‑1 blockade compared with mock tumors. At present, whether the FXR high PD‑L1 low phenotype predicts clinical response to immunotherapy in patients with NSCLC remains unclear. Herein, a retrospective study was conducted to examine the expression levels of FXR, PD‑L1 and CD8 + T cells by immunohistochemistry in a cohort of 149 patients with NSCLC receiving anti‑PD‑1‑based chemo‑immunotherapy. The results revealed that high FXR and PD‑L1 expression levels were associated with higher objective response rates (ORR) in all patients. High PD‑L1 expression also indicated superior progression‑free survival (PFS). Interestingly, an inverse correlation was identified between FXR and PD‑L1 expression in specimens with NSCLC. Subgroup analysis revealed that high FXR expression was associated with a higher ORR, as well as longer PFS and overall survival (OS) in PD‑L1 low patients. Cox multivariate analysis revealed that high FXR expression was an independent predictor for PFS and OS in PD‑L1 low patients. Tumor microenvironment evaluation revealed a statistically significant decrease of infiltrating CD8 + T cells in FXR high specimens with NSCLC. Overall, the present study proposed an FXR high PD‑L1 low signature as a candidate predictor of response to anti‑PD‑1‑based chemo‑immunotherapy in PD‑L1 low/negative patients with NSCLC, providing evidence that could be used to broaden the patients benefitting from immunotherapy.

Diabetes is associated with several diabetic-related abnormalities which increase the risk of onset or worsening of heart failure. Recent studies showed that the majority of diabetic patients present with heart failure with preserved ejection fraction (HFpEF), and the prevalence of HFpEF in diabetics is alarming. Moreover, outcomes in HFpEF are poor and could be compared to those of heart failure with reduced ejection fraction (HFrEF), with 1-year mortality ranging between 10 and 30%. In contrast to HFrEF, there is very limited evidence for pharmacologic therapy in symptomatic patients with preserved ejection fraction, and therefore, the optimal selection of treatment for diabetic HFpEF remains challenging. This narrative review article summarizes the currently available data on the pharmacological treatment of HFpEF in patients with diabetes., Competing Interests: Jakub Benko, Matej Samoš, Tomáš Bolek, Dana Prídavková, Jakub Jurica, Martin Jozef Péč, Peter Galajda, and Marián Mokáň have no conflicts of interest to declare, (Copyright © 2022 Jakub Benko et al.)

Technological advances have made it possible to offer home-based chemotherapy to patients without health care professionals being present. Prior studies on effects of home-based treatment lack inclusion of patients with hematologic malignancies. We present data from a multicenter single-arm feasibility and safety study of home-based intensive chemotherapy in patients with newly diagnosed acute myeloid leukemia and their quality of life and psychological wellbeing. This national study included patients from six sites in Denmark who received intensive chemotherapy on programmed CADD Solis infusion pumps through a central venous catheter and were also managed as outpatients during treatment-induced pancytopenia. Data are presented from 104 patients, receiving 272 treatments with 1.096 (mean 4.57, SD 3.0) home infusion days out of 1.644 treatment days (67 %). Sixty-two of 168 (36.9 %) reinduction and consolidation treatment cycles ensuing pancytopenia phases were solely handled in the outpatient clinic. Patients reported high satisfaction with home-based treatment, which had a positive influence on their ability to be involved in their treatment and be socially and physically active. No unexpected events occurred during the intervention. Overall, patients improved in all quality of life outcomes over time. Home-based intensive chemotherapy treatment was feasible and safe in this population. ClinicalTrials.gov identifier: NCT04904211., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Circulating tumor DNA (ctDNA) has potential as a specific, noninvasive, and cost-effective new biomarker for patients with lung cancer. This study aimed to determine whether plasma ctDNA can be used to predict treatment outcomes in patients with lung cancer., Methods: Pre- and in-treatment blood samples were collected from 14 patients with lung cancer receiving chemotherapy. Based on next-generation sequencing technology, we constructed a unique molecular identifier (UMI) library and performed targeted deep sequencing of 72 genes (15 000×). We used dVAF to evaluate the change level and trend of variant allele frequency (VAF)., Results: We identified MUC16, KMT2D, AMER1, and NTRK1 as the most-frequently mutated genes in ctDNA associated with lung cancer. Furthermore, we showed that the change trend of dVAF in patients with lung cancer undergoing chemotherapy was closely related to the changes in both tumor volume and tumor biomarkers, including CEA, CA125, NSE, and CK (Cytokeratin). Moreover, the ctDNA analysis revealed disease progression of SCLC patients earlier than did computed tomography., Conclusions: The dynamic detection of plasma ctDNA VAF has the potential value as a biomarker for evaluating the efficacy of chemotherapy in patients with SCLC and advanced NSCLC, and may predict the progression of lung cancer patients earlier than radiography., (© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Tobacco use disorder is highly prevalent; more than a billion individuals use tobacco worldwide. Popular views on the addictive potential of tobacco often underestimate the complex neural adaptations that underpin continued use. Although sometimes trivialized as a minor substance, effects of nicotine on behavior lead to profound morbidity over a lifetime of exposure. Innovations in processing have led to potent forms of tobacco and delivery devices. Proactive treatment strategies focus on pharmacotherapeutic interventions. Innovations on the horizon hold promise to help clinicians address this problem in a phenotypically tailored manner. Efforts are needed to prevent tobacco use for future generations., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting adverse reaction in cancer patients treated with several cytotoxic anticancer agents including paclitaxel. Duloxetine, an antidepressant known as a serotonin-noradrenalin reuptake inhibitor, is the only agent that has moderate evidence for the use to treat painful CIPN. The present retrospective cohort study aimed to analyze risk factors for paclitaxel-induced peripheral neuropathy (PIPN), and investigate ongoing prescription drug use for PIPN in Japan. Female breast and gynecologic cancer patients who underwent paclitaxel-based chemotherapy at a single center in Japan between January 2016 and December 2019 were enrolled in this study. Patients' information obtained from electronic medical records were statistically analyzed to test possible risk factors on PIPN diagnosis. Patients' age, total paclitaxel dose, the history of female hormone-related diseases, hypertension and body mass index (BMI), but not additional platinum agents, were significantly associated with increased PIPN diagnosis. Drugs prescribed for PIPN included duloxetine, pregabalin, mecobalamin and Goshajinkigan, a polyherbal medicine, regardless of poor evidence for their effectiveness against CIPN, and were greatly different between breast and gynecologic cancer patients diagnosed with PIPN at the departments of Surgery and Gynecology, respectively. Thus, older age, greater total paclitaxel dose, the history of estrogen-related diseases, hypertension and BMI are considered risk factors for PIPN in paclitaxel-based chemotherapy of female cancer patients. It appears an urgent need to establish a guideline of evidence-based pharmacotherapy for PIPN., Competing Interests: The authors have declared that no competing interests exist.

Flavonoids are polyphenolic plant secondary metabolites with pleiotropic biological properties, including anti-cancer activities. These natural compounds have potential utility in glioblastoma (GBM), a malignant central nervous system tumor derived from astrocytes. Conventional GBM treatment modalities such as chemotherapy, radiation therapy, and surgical tumor resection are beneficial but limited by extensive tumor invasion and drug/radiation resistance. Therefore, dietary flavonoids-with demonstrated anti-GBM properties in preclinical research-are potential alternative therapies. This review explores the synergistic enhancement of the anti-GBM effects of conventional chemotherapeutic drugs by flavonoids. Primary studies published between 2011 and 2021 on flavonoid-chemotherapeutic synergy in GBM were obtained from PubMed. These studies demonstrate that flavonoids such as chrysin, epigallocatechin-3-gallate (EGCG), formononetin, hispidulin, icariin, quercetin, rutin, and silibinin synergistically enhance the effects of canonical chemotherapeutics. These beneficial effects are mediated by the modulation of intracellular signaling mechanisms related to apoptosis, proliferation, autophagy, motility, and chemoresistance. In this light, flavonoids hold promise in improving current therapeutic strategies and ultimately overcoming GBM drug resistance. However, despite positive preclinical results, further investigations are necessary before the commencement of clinical trials. Key considerations include the bioavailability, blood-brain barrier (BBB) permeability, and safety of flavonoids; optimal dosages of flavonoids and chemotherapeutics; drug delivery platforms; and the potential for adverse interactions.

Development of combination therapy to decrease side effects of chemotherapeutic drugs and increase their utilization rate in combination with gene editing is a key research topic in tumor treatment. The present study aimed to investigate the effect of cationic microbubbles (CMBs) carrying paclitaxel (PTX) and C‑erbB‑2 knockout plasmid on the endometrial cancer cell line HEC‑1A and to determine how C‑erbB‑2 regulates the function of endometrial cancer cells. Cells were treated with CMB, PTX, PTX‑CMBs, cationic plasmid‑carrying or cationic PTX‑carrying plasmid groups. After verifying the most effective combination of PTX‑CMBs and plasmids, HEC‑1A cells were transfected. Reverse transcription‑quantitative (RT‑q)PCR and western blotting were used to measure C‑erbB‑2 and protein expression. After verifying C‑erbB‑2 knockout, invasion, healing, clone formation and proliferation of HEC‑1A cells were assessed. Simultaneously, expression levels of the genes for P21, P27, mammalian target of rapamycin ( mTOR ), and Bcl‑2 associated death promoter ( Bad ) were measured by RT‑qPCR. Compared with the PTX group, CMBs significantly enhanced the absorption efficiency of PTX by HEC‑1A cells. C‑erbB‑2 knockout had an inhibitory effect on the proliferation, migration and invasion of HEC‑1A cells; cell proliferation and invasion of the group carrying PTX and plasmids simultaneously were significantly weakened. The C‑erbB‑2 ‑knockout group exhibited increased expression of  P21 and  P27 . Simultaneously loading PTX and plasmid may be novel combination therapy with great potential. C‑erbB‑2 may regulate the proliferation of HEC‑1A cells by downregulating expression of  P21 and  P27 .

Abundant existence of extracellular matrix biological hydrogels in solid tumors precludes most therapeutics to arrive at intracellular target sites, which is probably one of the threatened reasons of pancreatic ductal adenocarcinoma (PDAC) for public health. In this study, we designed a rod-shaped protocell nanoparticle loading with doxorubicin hydrochloride (Dox) and indocyanine green (ICG), denoted as Dox/ICG-RsPNs, for enhanced chemo-photothermal PDAC treatment. The enhanced therapeutic efficacy was achieved by successively enhancing penetration across matrix hydrogels, endocytosis, increasing local temperature under laser irradiation and hyperthermia-triggered Dox release to nucleus. We found that RsPNs with rod shape could easily penetrate across matrix hydrogel, exerting excellent tumor accumulation. Then RsPNs was internalized effectively by BxPC-3 cells via a caveolin-mediated endocytosis pathway. In addition, ICG endowed the Dox/ICG-RsPNs with photothermal effect and the photothermal conversion efficiency was calculated for 16.2%. Under irradiation, a great number of Dox transported to the nucleus via hyperthermia-induced release. Furthermore, we found that the relative tumor volume of Dox/ICG-RsPNs was merely 1.37 under irradiation at the end of pharmacodynamic studies, which was significantly lower than that of other groups. These findings will provide a promise on the rational design of drug delivery system for effective chemo-photothermal combination therapy to treat PDAC., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose: To investigate the survival benefit with first/second generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and osimertinib in different treatment sequences., Methods: We retrospectively screened 3807 patients diagnosed with cancer between 2013 and 2019 at Kaohsiung Chang Gung Memorial Hospital. In total, 76 patients with EGFR T790M mutation who received osimertinib after re-biopsy or liquid biopsy were enrolled for the analysis., Results: The median progression-free survival (PFS), median overall survival (OS), and median OS2 of the 76 patients were 11.93, 66.53, and 29.57 months, respectively. A significant difference was observed in the disease control rate between those who received osimertinib treatment after chemotherapy (group A) and those who received osimertinib immediately following EGFR-TKI therapy (group B) (34 [94.4%] vs. 31 [77.5%], p = 0.036). In addition, chronic obstructive pulmonary disease tended to be a poor prognostic factor for PFS and OS., Conclusion: This real-world analysis revealed that previous chemotherapy could affect the treatment outcomes of patients with non-small cell lung cancer treated with osimertinib. Osimertinib treatment following first/second generation EGFR-TKI treatment or chemotherapy resulted in improved survival benefit., (© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: The quantity of skeletal muscles has recently been reported to have prognostic value in patients with non-small-cell lung cancer (NSCLC) treated with second-line immunotherapy. However, the prognostic role of skeletal muscle assessment in NSCLC patients undergoing first-line immuno-oncology (IO) combinatorial treatment (IO-chemotherapy) has not been elucidated., Methods: We retrospectively reviewed 36 patients with NSCLC undergoing first-line IO-chemotherapy between April 2018 and June 2021 in our hospital. The cross-sectional area of the erector spinae muscle (ESM CSA ) was evaluated by manual tracing on computed tomography scans at the level of the 12th thoracic vertebra before initiating IO-chemotherapy. To minimize deviation due to physique, the ESM CSA was adjusted by body surface area (BSA) (ESM CSA to BSA ratio: ESM CSA /BSA). A survival time analysis was performed using the Kaplan-Meier method and log-rank test. A multivariate analysis with Cox proportional hazards model was conducted to investigate the prognostic value of the ESM CSA /BSA and inflammatory and nutritional indices., Results: The median progression-free survival (PFS) and overall survival (OS) were 6.5 and 16.6 months, respectively. Intergroup comparison by the log-rank test revealed that there was no significant difference in the median PFS, but the median OS was significantly long in the high ESM CSA /BSA (>19 cm 2/ m 2 ) (high ESM CSA /BSA group, p = 0.0373). The multivariate analysis showed that ESM CSA /BSA was an independent prognostic factor for OS (hazard ratio 0.79, p = 0.044)., Conclusions: The results of this study indicate that the pretreatment ESM CSA /BSA may be a potential prognostic factor in NSCLC patients receiving first-line IO-chemotherapy., (© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Objectives: Sinonasal mucosal melanoma (SNMM) is an aggressive cancer usually managed with surgical resection. This study evaluates the impact of treatment modality and positive surgical margin (PSM) on survival following resection of SNMM., Study Design: Retrospective study of a national cancer registry., Methods: The National Cancer Database was queried for cases of SNMM from 2010 to 2015. Data regarding patient demographics, tumor staging, and treatment modality were obtained. Survival rates were compared by margin status: PSM, negative (NSM), and no operation (0SM) using Kaplan-Meier analysis and log rank test., Results: A total of 446 patients met inclusion criteria. Most cases were elderly (>66 years-old) (67.3%), female (54.3%), and white (89.5%). Cases of SNMM most commonly involved the nasal cavity (81.6%), were Stage 3 (60.0%), and underwent surgical resection at an academic center (65.0%). NSM and PSM were present in 59.0% and 26.9% of cases, respectively, while 14.1% of cases did not undergo surgical resection (0SM). Factors predictive of PSM included resection at a community hospital (OR 2.47) and Stage 4 disease (OR 2.07). The 2-year survival rates were 72.1% (95% CI 69.4-75.4%), 36.3% (95% CI 22.0-48.9), and 16.0% (95% CI 8.2-25.4%) for NSM, PSM and 0SM, respectively. Survival was statistically significant between NSM and PSM (Log rank <0.001) but not between 0SM and PSM (Log rank = 0.062)., Conclusion: Our study emphasizes the need for NSM for SNMM as PSM did not demonstrate any significant improvement in survival when compared to 0SM. Our findings suggest that cases of SNMM are best managed at academic centers., Level of Evidence: 4 Laryngoscope, 131:2429-2435, 2021., (© 2021 The American Laryngological, Rhinological and Otological Society, Inc.)

In our body, all the cells are constantly sharing chemical and electrical information with other cells. This intercellular communication allows them to respond in a concerted way to changes in the extracellular milieu. Connexins are transmembrane proteins that have the particularity of forming two types of channels; hemichannels and gap junction channels. Under normal conditions, hemichannels allow the controlled release of signaling molecules to the extracellular milieu. However, under certain pathological conditions, over-activated hemichannels can induce and/or exacerbate symptoms. In the last decade, great efforts have been put into developing new tools that can modulate these over-activated hemichannels. Small molecules, antibodies and mimetic peptides have shown a potential for the treatment of human diseases. In this review, we summarize recent findings in the field of hemichannel modulation via specific tools, and how these tools could improve patient outcome in certain pathological conditions., (Copyright © 2021 Elsevier B.V. All rights reserved.)

In this study, we aimed to explore cyclophosphamide (Cytoxan) response-associated genes and constructed a model to predict the prognosis of breast cancer (BRCA) patients. Samples obtained from TCGA and GEO databases were subjected to Weighted Gene Coexpression Network Analysis (WGCNA) and univariate Cox and LASSO Cox regression analysis to identify and validate the Cytoxan response-related prognostic signature. Moreover, multivariate Cox regression analysis was performed to analyze the independence of factors, and the nomogram model was constructed by including all the independent factors. WGCNA revealed that 159 genes are significantly correlated with Cytoxan response in BRCA samples, and the samples with a different prognosis could be effectively distinguished based on the expression of those 159 genes. Ten genes were further selected to be related to the prognosis of BRCA patients, including PCDHB2 , GRIK2 , FRMD7 , CCSER1 , PCDHGA1 , PCDHA1 , LRRC37A6P , PCDHGA12 , ZNF486 , and PCDHGB5 , based on the Risk Score model. Among them, PCDHA1 expression was validated in cells and patient samples. Multivariate Cox regression analysis confirmed that the Risk Score is an independent factor. Furthermore, the nomogram model showed that the predicted survival probability is closely related to the actual survival probability. In conclusion, we identified 159 genes potentially correlated with the Cytoxan response of BRCA patients, which had prognostic value in BRCA.

PINK1 , also known as PARK6 , is a PTEN -induced putative kinase 1 that is encoded by nuclear genes. PINK1 is ubiquitously expressed and regulates mitochondrial function and mitophagy in a range of cell types. The dysregulation of PINK1 is associated with the pathogenesis and development of mitochondrial-associated disorders. Many natural products could regulate PINK1 to relieve PINK1-associated diseases. Here, we review the structure and function of PINK1, its relationship to human diseases, and the regulation of natural products to PINK1. We further highlight that the discovery of natural PINK1 regulators represents an attractive strategy for the treatment of PINK1-related diseases, including liver and heart diseases, cancer, and Parkinson's disease. Moreover, investigating PINK1 regulation of natural products can enhance the in-depth comprehension of the mechanism of action of natural products., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2021 Yan-Qin Li et al.)

Background: The use of magnetic nanozymes (NZs) with the ability to synchronize gas therapy through photodynamic and chemotherapy in the treatment of breast cancer has received much attention., Results: Hence, in this study, we designed a bovine lactoferrin-coated iron sulfide NZs containing doxorubicin (abbreviated as: FeS-Dox@bLf NZs) by wet-chemical synthesis method. Then, the physicochemical characteristics of synthesized NZs were explored by several methods. Also, the level of Fe 2+ , H 2 S and Dox releases from FeS-Dox@Lf NZs. Also, the cytotoxic effects of FeS-Dox@Lf NZs were investigated by cellular assays. After intravenous injections of NZs and laser irradiation, significant effects of FeS-Dox@Lf NZs on mice weight and tumor status were observed. Afterwards, not only the distribution of Dox in the body was examined by fluorescent, but also the time of Fe clearance and the amount of Dox and Fe retention in vital tissues were determined. The findings confirm that FeS-Dox@Lf NZs, in addition to targeted drug distribution in tumor tissue, resulted in superior therapeutic performance compared to free Dox due to reduced Dox side effects in vital tissues, and increased level of free radicals in 4T1 cells., Conclusion: Overall, FeS-Dox@Lf NZs with the ability to synchronize chemotherapy and gas therapy raised hopes for more effective treatment of breast cancer., (© 2021. The Author(s).)

Importance: Pediatric acute myeloid leukemia (AML) requires multiple courses of intensive chemotherapy that result in neutropenia, with significant risk for infectious complications. Supportive care guidelines recommend hospitalization until neutrophil recovery. However, there are little data to support inpatient over outpatient management., Objective: To evaluate outpatient vs inpatient neutropenia management for pediatric AML., Design, Setting, and Participants: This cohort study used qualitative and quantitative methods to compare medical outcomes, patient health-related quality of life (HRQOL), and patient and family perceptions between outpatient and inpatient neutropenia management. The study included patients from 17 US pediatric hospitals with frontline chemotherapy start dates ranging from January 2011 to July 2019, although the specific date ranges differed for the individual analyses by design and relative timing. Data were analyzed from August 2019 to February 2020., Exposures: Discharge to outpatient vs inpatient neutropenia management., Main Outcomes and Measures: The primary outcomes of interest were course-specific bacteremia incidence, times to next course, and patient HRQOL. Course-specific mortality was a secondary medical outcome., Results: Primary quantitative analyses included 554 patients (272 [49.1%] girls and 282 [50.9%] boys; mean [SD] age, 8.2 [6.1] years). Bacteremia incidence was not significantly different during outpatient vs inpatient management (67 courses [23.8%] vs 265 courses [29.0%]; adjusted rate ratio, 0.73; 95% CI, 0.56 to 1.06; P = .08). Outpatient management was not associated with delays to the next course compared with inpatient management (mean [SD] 30.7 [12.2] days vs 32.8 [9.7] days; adjusted mean difference, -2.2; 95% CI, -4.1 to -0.2, P = .03). Mortality during intensification II was higher for patients who received outpatient management compared with those who received inpatient management (3 patients [5.4%] vs 1 patient [0.5%]; P = .03), but comparable with inpatient management at other courses (eg, 0 patients vs 5 patients [1.3%] during induction I; P = .59). Among 97 patients evaluated for HRQOL, outcomes did not differ between outpatient and inpatient management (mean [SD] Pediatric Quality of Life Inventory total score, 70.1 [18.9] vs 68.7 [19.4]; adjusted mean difference, -2.8; 95% CI, -11.2 to 5.6). A total of 86 respondents (20 [23.3%] in outpatient management, 66 [76.7%] in inpatient management) completed qualitative interviews. Independent of management strategy received, 74 respondents (86.0%) expressed satisfaction with their experience. Concerns for hospital-associated infections among caregivers (6 of 7 caregiver respondents [85.7%] who were dissatisfied with inpatient management) and family separation (2 of 2 patient respondents [100%] who were dissatisfied with inpatient management) drove dissatisfaction with inpatient management. Stress of caring for a neutropenic child at home (3 of 3 respondents [100%] who were dissatisfied with outpatient management) drove dissatisfaction with outpatient management., Conclusions and Relevance: This cohort study found that outpatient neutropenia management was not associated with higher bacteremia incidence, treatment delays, or worse HRQOL compared with inpatient neutropenia management among pediatric patients with AML. While outpatient management may be safe for many patients, course-specific mortality differences suggest that outpatient management in intensification II should be approached with caution. Patient and family experiences varied, suggesting that outpatient management may be preferred by some but may not be feasible for all families. Further studies to refine and standardize safe outpatient management practices are warranted.

Objective: When treated for childhood cancers, at least 50% of children exposed to platinum agents have permanent hearing loss. We determined the relative risk of childhood hearing loss after in utero exposure to platinum chemotherapy in our registry cohort., Method: After exposure to platinum chemotherapy in utero, all children undergo routine newborn hearing screening. This consists of Otoacoustic Emissions. Children who failed this screen were evaluated by audiologists. For those children with hearing loss by Automated Auditory Brainstem Response, prenatal and postnatal treatment details were compared to platinum exposed children without hearing loss., Results: Three hundred and seven children were exposed to chemotherapy in utero. Four children were diagnosed with hearing loss, all exposed to platinum agents. Chemotherapy exposures included: Cisplatin/Paclitaxel (2), Etoposide/Cisplatin/Bleomycin (1), Carboplatin/Paclitaxel (1) to treat ovarian (2), or cervical cancer (2). Of the 39 platinum exposed without hearing loss: 11 children were exposed to oxaliplatin, 16 were exposed to cisplatin and 12 to carboplatin in utero. Two hundred and sixty four women received non-platinum based chemotherapy for various cancers during pregnancy. Among these, there were no cases of hearing loss. There was a significant difference in hearing loss based on exposure to platinum agents in utero compared to non-platinum-containing chemotherapy regimens, 4/43 versus 0/264, p = 0.0003. There were no statistical differences in prenatal and postnatal treatment details, including: gestational age at diagnosis, at first chemotherapy treatment, at first platinum treatment, at delivery (<32 weeks, <35 weeks, <37 weeks), gender, birthweight, birthweight percentile, rates of intrauterine growth restriction, neonatal complications or use of postnatal antibiotics between the platinum exposed children with and without hearing loss., Conclusion: The only children in the registry exposed to chemotherapy who were diagnosed with hearing loss had been exposed to cisplatin or carboplatin in utero. No hearing loss occurred in children exposed to oxaliplatin, or non-platinum agents. Due to a concern for cisplatin ototoxicity, carboplatin is the preferred platinum agent for use in pregnancy when equivalent maternal survival can be expected for the particular cancer type. For newborns exposed to platinum agents in utero, newborn screening with an auditory emissions test at birth (OES) may not detect sensorineural hearing loss and auditory brainstem response testing is recommended, regardless of the newborn screening result., (© 2021 John Wiley & Sons Ltd.)

The multiple diagnosis and treatment mechanisms of chemotherapy combined with photothermal/photodynamic therapy have very large application prospects in the field of cancer treatment. Therefore, in order to achieve effective and safe antitumour treatment, it is necessary to design an intelligent responsive polymer nanoplatform as a drug delivery system. Herein, the thermosensitive poly-N-isopropylacrylamide (PNIPAM) nanogel particles were prepared by soap-free emulsion polymerization and loaded with a large amount of photosensitizer indocyanine green (ICG) and anticarcinogen 5-fluorouracil (5-Fu), which effectively to realize the cooperative chemotherapy and photothermal/photodynamic therapy for tumours. The 5-Fu@ICG-PNIPAM nanogels significantly improved the bioavailability of the drug and achieved controlled release. In addition, under near-infrared laser (NIR) irradiation at 808 nm, 5-Fu@ICG-PNIPAM nanogels generated lots of heat and reactive oxygen, which significantly enhanced cellular uptake and in vitro antitumour treatment effects. The results showed that 5-Fu@ICG-PNIPAM nanogels were effectively endocytosed by HeLa cells, which also enhanced the drug's entrance into the nucleus. Moreover, compared with alone chemotherapy or photothermal/photodynamic therapy, 5-Fu@ICG-PNIPAM nanogels significantly increased cytotoxicity under NIR irradiation, suggesting that chemotherapy and photothermal/photodynamic synergistic therapy had excellent antitumour properties. Therefore, this temperature-responsive nanogel platform probably has great application prospects in clinical antitumour treatment.

Competing Interests: Conflict of interest J. Bridgewater declares consulting or advisory roles for Merck Serono, SERVIER, Roche, Bayer, AstraZeneca, Incyte and Basilea; travel support from MSD Oncology, Merck Serono, Servier and BMS. Please refer to the accompanying ICMJE disclosure forms for further details.

Background: In comparison with traditional therapeutics, it is highly preferable to develop a combinatorial therapeutic modality for nanomedicine and photothermal hyperthermia to achieve safe, efficient, and localized delivery of chemotherapeutic drugs into tumor tissues and exert tumor-activated nanotherapy. Biocompatible organic-inorganic hybrid hollow mesoporous organosilica nanoparticles (HMONs) have shown high performance in molecular imaging and drug delivery as compared to other inorganic nanosystems. Disulfiram (DSF), an alcohol-abuse drug, can act as a chemotherapeutic agent according to its recently reported effectiveness for cancer chemotherapy, whose activity strongly depends on copper ions., Results: In this work, a therapeutic construction with high biosafety and efficiency was proposed and developed for synergistic tumor-activated and photothermal-augmented chemotherapy in breast tumor eradication both in vitro and in vivo. The proposed strategy is based on the employment of HMONs to integrate ultrasmall photothermal CuS particles onto the surface of the organosilica and the molecular drug DSF inside the mesopores and hollow interior. The ultrasmall CuS acted as both photothermal agent under near-infrared (NIR) irradiation for photonic tumor hyperthermia and Cu 2+ self-supplier in an acidic tumor microenvironment to activate the nontoxic DSF drug into a highly toxic diethyldithiocarbamate (DTC)-copper complex for enhanced DSF chemotherapy, which effectively achieved a remarkable synergistic in-situ anticancer outcome with minimal side effects., Conclusion: This work provides a representative paradigm on the engineering of combinatorial therapeutic nanomedicine with both exogenous response for photonic tumor ablation and endogenous tumor microenvironment-responsive in-situ toxicity activation of a molecular drug (DSF) for augmented tumor chemotherapy., (© 2021. The Author(s).)

Background: Non-small-cell lung cancer (NSCLC) is a major health burden in many countries. This review aimed to evaluate the efficacy of traditional herbal medicine (THM) combined with first-line platinum-based chemotherapy (PBCT) for the treatment of advanced NSCLC., Methods: From inception to April 2021, relevant studies were retrieved from 9 electronic databases. Randomized controlled trials (RCTs) comparing survival outcomes of THM + PBCT treatment with PBCT treatment in patients with advanced NSCLC were reviewed. The risk of bias was evaluated using the Cochrane Risk of Bias Tool. Overall survival, 1-year survival, progression-free survival or time to progression, tumor response rate, and adverse effects were analyzed., Results: Sixteen RCTs comprising 1445 patients were included. The meta-analysis indicated that THM + PBCT treatment, compared to PBCT alone, could improve overall survival (median survival ratio = 1.24, 95% confidence intervals [CI] [1.11, 1.39], P < .001), progression-free survival/time to progression (median survival ratio = 1.22, 95% CI [1.09, 1.37], P < .001), and the 1-year survival rate (risk ratio [RR] = 1.56, 95% CI [1.31, 1.86], P < .001). THM + PBCT also led to a higher tumor response rate (RR = 1.39, 95% CI [1.22, 1.59], P < .001) and lower incidence of thrombocytopenia (RR = 0.72, 95% CI [0.56, 0.92], P = .009) and nausea/vomiting (RR = 0.35, 95% CI [0.21, 0.57], P < .001), while there was no significant effect observed on leukopenia (RR = 0.68, 95% CI [0.34, 1.36], P = .27)., Conclusion: THM, when used in combination with PBCT, might increase survival and the tumor response rate while decreasing the side effects caused by chemotherapy in patients with advanced NSCLC. However, considering the limited methodological qualities of the included trials, more rigorous RCTs are needed., Competing Interests: The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

In the SIOP Wilms' tumor (WT) studies, preoperative chemotherapy is used as primary treatment, and tumors are classified thereafter by pathologists. Completely necrotic WTs (CN-WTs) are classified as low-risk tumors. The aim of the study was to evaluate whether a subset of regressive type WTs (RT-WTs) (67%-99% chemotherapy-induced changes [CIC]) showing an exceptionally good response to preoperative chemotherapy had comparably excellent survivals as CN-WTs, and to establish a cut-off point of CIC that could define this subset. The study included 2117 patients with unilateral, nonanaplastic WTs from the UK-CCLG and GPOH-WT studies (2001-2020) treated according to the SIOP-WT-2001 protocol. There were 126 patients with CN-WTs and 773 with RT-WTs, stages I-IV. RT-WTs were subdivided into subtotally necrotic WTs (>95% CIC) (STN-WT96-99) (124 patients) and the remaining of RT-WT (RR-WT67-95) (649 patients). The 5-year event-free survival (EFS) and overall survival (OS) for CN-WTs were 95.3% (±2.1% SE) and 97.3% (±1.5% SE), and for RT-WTs 85.7% (±1.14% SE, P < .01) and 95.2% (±0.01% SE, P = .59), respectively. CN-WT and STN-WT96-99 groups showed significantly better EFS than RR-WT67-95 (P = .003 and P = .02, respectively), which remained significantly superior when adjusted for age, local stage and metastasis at diagnosis, in multivariate analysis, whereas OS were superimposable (97.3 ± 1.5% SE for CN-WT; 97.8 ± 1.5% SE for STN-WT96-99; 94.7 ± 1.0% SE for RR-WT67-95). Patients with STN-WT96-99 share the same excellent EFS and OS as patients with CN-WTs, and although this was achieved by more treatment for patients with STN-WT96-99 than for patients with CN-WT, reduction in postoperative treatment of these patients may be justified., (© 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Mitotic errors lead to aneuploidy, a condition of karyotype imbalance, frequently found in cancer cells. Alterations in chromosome copy number induce a wide variety of cellular stresses, including genome instability. Here, we show that cancer cells might exploit aneuploidy-induced genome instability and the resulting gene copy-number changes to survive under conditions of selective pressure, such as chemotherapy. Resistance to chemotherapeutic drugs was dictated by the acquisition of recurrent karyotypes, indicating that gene dosage might play a role in driving chemoresistance. Thus, our study establishes a causal link between aneuploidy-driven changes in gene copy number and chemoresistance and might explain why some chemotherapies fail to succeed., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The in-silico development of a chemotherapeutic dosing schedule for treating cancer relies upon a parameterization of a particular tumour growth model to describe the dynamics of the cancer in response to the dose of the drug. In practice, it is often prohibitively difficult to ensure the validity of patient-specific parameterizations of these models for any particular patient. As a result, sensitivities to these particular parameters can result in therapeutic dosing schedules that are optimal in principle not performing well on particular patients. In this study, we demonstrate that chemotherapeutic dosing strategies learned via reinforcement learning methods are more robust to perturbations in patient-specific parameter values than those learned via classical optimal control methods. By training a reinforcement learning agent on mean-value parameters and allowing the agent periodic access to a more easily measurable metric, relative bone marrow density, for the purpose of optimizing dose schedule while reducing drug toxicity, we are able to develop drug dosing schedules that outperform schedules learned via classical optimal control methods, even when such methods are allowed to leverage the same bone marrow measurements., (© 2021. The Author(s).)

Objective/hypothesis: To estimate the prevalence of baseline clinically significant distress (distress score ≥ 4) in head and neck cancer patients planned and treated with radical intent radiotherapy using the National Comprehensive Cancer Network Distress Thermometer (DT) and assess factors predictive of distress., Study Design: Cross-sectional study., Methods: This was a cross-sectional study evaluating distress in 600 head and neck cancer patients undergoing radiation therapy. The DT was used to screen patients for distress at baseline before radiotherapy., Results: The median distress score of the entire cohort was 4 interquartile range (IQR) (IQR: 3-5), and 340 patients (56.7%) had clinically significant distress. On univariate analysis, the causal factors predictive of distress were low socioeconomic status (P = .04), presence of proliferative growth at presentation (P = .008), site of the tumor (oral cavity, P = .02), comorbidity (P = .04), and presence of Ryle's tube or tracheostomy tube at baseline (P = .01). Low socioeconomic status was significant (P = .04) on multivariate analysis for high levels of distress., Conclusions: Among head and neck cancer patients, 56% of patients had clinically significant baseline distress, and patients with low socioeconomic status had high distress. There is a need for interventions to mitigate distress., Level of Evidence: 4 Laryngoscope, 131:2023-2029, 2021., (© 2021 The American Laryngological, Rhinological and Otological Society, Inc..)

The nCOVID-19 pandemic initiated its course of contagion from the city of Wuhan and now it has spread all over the globe. SARS-CoV-2 is the causative virus and the infection as well as its symptoms are distributed across the multi-organ perimeters. Interactions between the host and virus governs the induction of 'cytokine storm' resulting various immunopathological consequences leading to death. Till now it has caused tens of millions of casualties and yet no credible cure has emerged to vision. This article presents a comprehensive overview on the two most promising remedial approaches that are being attempted for the management, treatment, and plausible cure of nCOVID-19. In this context, chemotherapeutic approach primarily aims to interrupt the interactions between the host and the virus causing inhibition of its entry into the host cell and/or its proliferation and suppressing the inflammatory milieu in the infected patients. On the other side, immunotherapeutic approaches aim to modulate the host immunity by fine tuning the inflammatory signaling cascades to achieve phylaxis from the virus and restoring immune-homeostasis. Considering most of the path-breaking findings, combinatorial therapy involving of chemotherapeutics as well as vaccine could usher to be a hope for all of us to eradicate the crisis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

We aimed to compare the sperm quality in different cancer types and benign diseases before gonadotoxic treatment, and assess the usage rate of cryopreserved sperm for assisted reproductive treatment (ART). This retrospective study was conducted at two university clinics between January 2008 and July 2018. A total of 545 patients suffering from cancer or benign diseases were included in the study. The pretreatment sperm analyses were based on the World Health Organization (WHO) guidelines. Patients with testicular malignancy (TM) showed a significantly lower sperm count (median [interquartile range]: 18.7 × 10 6 [5.3 × 10 6 -43.0 × 10 6 ] ml -1 ; P = 0.03) as well as total sperm count (42.4 × 10 6 [13.3 × 10 6 -108.5 × 10 6 ] per ejaculate; P = 0.007) compared to other malignant and benign diseases. In addition, patients with nonseminomatous TM showed the lowest sperm count (14.3 × 10 6 [6.0 × 10 6 -29.9 × 10 6 ] ml -1 , vs seminomas: 16.5 × 10 6 [4.6 × 10 6 -20.3 × 10 6 ] ml -1 ; P = 0.001). With reference to the WHO 2010 guidelines, approximately 48.0% of the patients with TM and 23.0% with hematological malignancies (HM) had oligozoospermia. During the observation period, only 29 patients (5.3%) used their frozen sperms for 48 ART cycles, resulting in 15 clinical pregnancies and 10 live births. The sperm quality varies with the type of underlying disease, with TM and HM patients showing the lowest sperm counts. Due to the observed low usage rate of cryopreserved sperm, further patient interviews and sperm analyses should be included in the routine oncologic protocols to avoid unnecessary storage expenses. However, sperm banking is worth the effort as it provides hope for men who cannot reproduce naturally after gonadotoxic treatment., Competing Interests: None

Chemotherapy-induced intestinal mucositis, a painful debilitating condition affecting up to 40-100% of patients undergoing chemotherapy, can reduce the patients' quality of life, add health care costs and even postpone cancer treatment. In recent years, the relationships between intestinal microbiota dysbiosis and mucositis have drawn much attention in mucositis research. Chemotherapy can shape intestinal microbiota, which, in turn, can aggravate the mucositis through toll-like receptor (TLR) signaling pathways, leading to an increased expression of inflammatory mediators and elevated epithelial cell apoptosis but decreased epithelial cell differentiation and mucosal regeneration. This review summarizes relevant studies related to the relationships of mucositis with chemotherapy regimens, microbiota, TLRs, inflammatory mediators, and intestinal homeostasis, aiming to explore how gut microbiota affects the pathogenesis of mucositis and provides potential new strategies for mucositis alleviation and treatment and development of new therapies.

Abstract: Breast cancer is the leading type of cancer among women worldwide, and a high number of breast cancer patients are suffering from psychological and cognitive disorders. This cross-sectional study used resting-state functional magnetic resonance imaging (rs-fMRI) and clinical neuropsychological tests to evaluate the possible underlying mechanisms.We enrolled 32 breast cancer patients without chemotherapy (BC), 32 breast cancer patients within 6 to 12 months after the completion of chemotherapy (BC&#95;CTx) and 46 healthy controls. Participants underwent neuropsychological tests and rs-fMRI with mean fractional amplitude of low-frequency fluctuation and mean regional homogeneity analyses. Between groups whole-brain voxel-wise rs-fMRI comparisons were calculated using two-sample t test. rs-fMRI and neuropsychological tests correlation analyses were calculated using multiple regression. Age and years of education were used as covariates. A false discovery rate-corrected P-value of less than .05 was considered statistically significant.We found significantly alteration of mean fractional amplitude of low-frequency fluctuation and mean regional homogeneity in the frontoparietal lobe and occipital lobe in the BC group compared with the other 2 groups, indicating alteration of functional dorsal attention network (DAN). Furthermore, we found the DAN alteration was correlated with neuropsychological impairment.The majority of potential underlying mechanisms of DAN alteration in BC patients may due to insufficient frontoparietal lobe neural activity to drive DAN and may be related to the effects of neuropsychological distress. Further longitudinal studies with comprehensive images and neuropsychological tests correlations are recommended., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: This study is aimed at examining the buffering effect of sense of coherence (SOC) on symptom distress during cancer drug therapy, which thereby affects health-related quality of life (QoL), and obtaining suggestions for promoting supportive care., Methods: We investigated health-related QoL (SF-8), symptom distress (using the Symptom Distress Scale (SDS)), and SOC (the SOC 13-item Scale) in 66 patients receiving adjuvant chemotherapy for non-small cell lung cancer. We employed descriptive statistics to seek the correlation of each variable; then, a hierarchical multiple regression analysis was conducted with SF-8 score as the dependent variable., Results: Results showed that significant changes in bodily pain showed a buffering effect on the SDS and sense of comprehensibility (β = - 0.658, p < 0.01, β = - 0.319, p < 0.05), sense of manageability (β = - 0.658, p < 0.01, β = 0.398, p < 0.01), and meaningfulness (β = - 0.658, p < 0.01, β = - 0.257, p < 0.05). Significant changes in general health perception showed a buffering effect on the SDS and sense of manageability (β = - 0.406, p < 0.01, β = 0.329, p < 0.05). As a result of the simple inclination test, SOC proved to be effective under high levels of symptom distress; the buffering effect of sense of manageability was reversed regarding bodily pain; and when meaningfulness was lower, it had a positive effect on QoL., Conclusion: This study revealed that SOC exerts a buffering effect in situations where symptoms are highly painful. It also revealed that the effect of SOC was reversed for bodily pain and that a high SOC had a negative effect on QoL.

FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus bevacizumab is the preferred first-line treatment for right-sided metastatic colorectal cancer with RAS mutation. However, severe adverse events are common in Japanese patients. We report the successful management of multiple stage IV colorectal cancers in a patient who received multidisciplinary treatment, including chemotherapy and Japanese Kampo medicine. A 68-year-old man presented with epigastralgia and appetite loss and was diagnosed with multiple stage IV colorectal cancers. Colonoscopy identified type II tumors in the ascending colon, sigmoid colon, and upper rectum. Histopathological examination of a biopsy specimen revealed well- to moderately differentiated tubular adenocarcinoma. Enhanced computed tomography of the thorax and abdomen showed multiple pulmonary nodules and para-aortic lymph node swelling. Laparoscopic loop-ileostomy was performed to avoid bowel obstruction due to severe stenosis of ascending colon cancer. Intraoperative observation revealed two white nodules suggestive of metastasis in the lateral area of the liver. Therefore, we diagnosed multiple stage IV colorectal cancers with multiple metastases (lung, liver, and distant lymph nodes). His postoperative course was uneventful, and chemotherapy was started. Since the cancer cells harbored a RAS mutation, he received FOLFOXIRI plus bevacizumab. Japanese Kampo medicine consisting of Hangeshashinto and Juzen-taiho-to, to prevent diarrhea and fatigue, was administered daily. After 12 courses of chemotherapy, though circumferential stenosis still existed in the ascending colon, the tumors in the sigmoid colon and upper rectum were unclear. Enhanced computed tomography showed shrinkage of the pulmonary nodules and para-aortic lymph node; therefore, laparoscopic-assisted ileocecal resection was performed. The postoperative histopathological examination revealed moderately differentiated adenocarcinoma. The patient recovered uneventfully, and Kampo medicine consisting of Ninjin'yoeito was administered for postoperative weakness. Administration of adjuvant chemotherapy in this patient led to a near complete response that has been maintained without recurrence for 2 years and 8 months without reduced quality of life., (Copyright © 2021. Published by Elsevier Ltd.)

Professor Henry Higgins in My Fair Lady said, 'Why can't a woman be more like a man?' Perhaps unintended, such narration extends to the reality of current drug development. A clear sex-gap exists in pharmaceutical research spanning from preclinical studies, clinical trials to post-marketing surveillance with a bias towards males. Consequently, women experience adverse drug reactions from approved drug products more often than men. Distinct differences in pharmaceutical response across drug classes and the lack of understanding of disease pathophysiology also exists between the sexes, often leading to suboptimal drug therapy in women. This review explores the influence of sex as a biological variable in drug delivery, pharmacokinetic response and overall efficacy in the context of pharmaceutical research and practice in the clinic. Prospective recommendations are provided to guide researchers towards the consideration of sex differences in methodologies and analyses. The promotion of disaggregating data according to sex to strengthen scientific rigour, encouraging innovation through the personalisation of medicines and adopting machine learning algorithms is vital for optimised drug development in the sexes and population health equity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier B.V.)

Background: Advanced non-small cell lung cancer (NSCLC) accounts for a high proportion of lung cancer cases. Targeted therapy improve the survival in these patients, but acquired drug resistance will inevitably occur. If tumor downstaging is achieved after targeted therapy, could surgical resection before drug resistance improve clinical benefits for patients with advanced NSCLC? Here, we conducted a clinical trial showing that for patients with advanced driver gene mutant NSCLC who did not progress after targeted therapy, salvage surgery (SS) could improve progression-free survival (PFS). Herein, we retrospectively reviewed our former clinical trial and thoracic cancer database in our medical institutions., Methods: We identified patients with advanced driver gene mutant NSCLC treated with targeted therapy plus SS or targeted therapy alone in our former clinical trial and our thoracic cancer database from July 2016 to July 2019. PFS was compared between the targeted therapy plus SS group and the targeted therapy only group using the log-rank test., Results: We identified 73 patients with driver gene mutant NSCLC who were treated with targeted therapy and 18 treated with targeted therapy plus SS.Among the 18 patients treated with targeted therapy plus SS, there were no obvious perioperative complications and deaths. Targeted therapy followed by SS resulted in a significantly longer PFS compared with targeted therapy alone (23.4 months VS 12.9 months, p = 0.0004)., Conclusions: Salvage surgery after tumor downstaging is a promising therapeutic strategy for some patients with advanced (stage IIIB-IV) NSCLC and may offer a new therapeutic option for multidisciplinary comprehensive treatment of lung cancer., (© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Abstract: The main purpose of this study was to investigate current state of constipation for lung cancer (LC) patients receiving platinum-based chemotherapy. The relationships between social demography, clinical variables, psychological status, and constipation were analyzed. In addition, quality of life (QoL) in LC patients with constipation was also analyzed. One hundred LC patients participated in this cross-sectional study. Under the guidance of the researchers, Functional Living Index-Emesis, Piper Fatigue Scale, Patient Health Questionnaire, Generalized Anxiety Disorder-7, European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 (version 3.0), Pittsburgh Sleep Quality Index, General Well-being Scale, Social Support Rate Scale, General Self-Efficacy Scale, and other related questionnaires were completed. The result showed the symptom of constipation was observed in 41 (41%) LC patients. The occurrence and development of constipation were associated with gender, food intake, exercise, nausea, fatigue, anxiety, depression, sleep disorders, and happiness. The study also found patients with constipation had significant lower QoL scores, especially the score in the general state. Constipation was very common in LC patients undergoing platinum-based chemotherapy. Reduced food intake and fatigue were the independent factors. Constipation significantly affects the QoL of the patients. Therefore, more attention should be paid to the risk factors of constipation in LC patients undergoing platinum-based chemotherapy, the earlier intervention was done to these patients, the better to improve their QoL., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Rationale: Near-Infrared persistent luminescence (NIR-PL) nanomaterials that can continually emit low-energy photons after ceasing excitation has emerged as a new generation of theranostic nanoparticle drug delivery systems (NDDSs) for imaging-guided cancer therapy, which stems from their special ability to completely avoid tissue autofluorescence interference. However, unresponsive diagnostic capability, inefficient drug delivery, and poor biodegradability limit the efficacy of most reported NIR-PL-based NDDSs. Methods: Herein, a multifaceted tumor microenvironment (TME)-degradable theranostic drug delivery nanocapsule based on an ultrasmall persistent phosphor with a hollow mesoporous manganese-doped, DOX-loaded silica shell (Mn-ZGOCS-PEG) is developed to overcome the above drawbacks. Results: We demonstrate that the well-designed nanocapsule enables tumor-responsive controlled drug release with ameliorated therapeutic efficacy, TME-responsive autofluorescence interference-free NIR-PL tracing, and manganese-enhanced magnetic resonance (Mn-MR) monitoring for practical dual-modality image-guided antitumor treatment in vivo . Conclusion: Our results indicate that Mn-ZGOCS-PEG nanocapsules enable tumor-targeting augmented chemotherapy under the guidance of TME-responsive dual-MR/NIR-PL-modality imaging in vivo . We believe that our work provides a new paradigm for the development of smart NIR-PL-based NDDSs with ultrasensitive multimodal diagnostic capability, enhanced anticancer effect, and efficient biodegradability., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Abstract: Currently, the impact of chemotherapy (CT) on survival outcomes in elderly patients with nasopharyngeal carcinoma (NPC) receiving radiation therapy (RT) remains controversial. This retrospective study aims to investigate survival outcomes in a cohort of elderly NPC patients receiving RT alone or together with CT.Clinical data on 529 NPC patients aged 65 years and older extracted from the Surveillance, Epidemiology, and End Results registry (2004-2015) was collected and retrospectively reviewed. In this cohort, 74 patients were treated with RT alone and 455 individuals received RT and CT. We used propensity score matching with a 1:3 ratio to identify correlations between patients based on 6 different variables. Kaplan-Meier analysis was used to evaluate overall (OS) and cancer-specific survival (CSS). The differences in OS and CSS between the 2 treatment groups were compared using the Log-rank test and Cox proportional hazards models.The estimated 5-year OS and CSS rates for all patients were 49.5% and 59.3%, respectively. The combination of RT and CT provided longer OS than RT alone (53.7% vs 36.9%, P = .002), while no significant difference was observed in CSS (61.8% vs 51.7%, P = .074) between the 2 groups. Moreover, multivariate analysis demonstrated that the combination of CT and RT correlated favorably with OS and CSS. Subgroup analyses showed that the combination of RT and CT correlated better with both OS and CSS in patients with stage T3 or N2 or stage III.Among NPC patients aged 65 years and older, treatment with RT and CT provided longer OS than RT alone. Furthermore, the combination of RT and CT showed a better correlation with OS and CSS in NPC patients with stage T3 or N2 or stage III., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Primary or acquired chemoresistance is a key link in the high mortality rate of ovarian cancer. There is no reliable method to predict chemoresistance in ovarian cancer. We hypothesized that specific methylation characteristics could distinguish chemoresistant and chemosensitive ovarian cancer patients., Methods: In this study, we used 450 K Infinium Methylation BeadChip to detect the different methylation CpGs between ovarian cancer patients. The differential methylation genes were analyzed by GO and KEGG Pathway bioinformatics analysis. The candidate CpGs were confirmed by pyrosequencing. The expression of abnormal methylation gene was identified by QRT-PCR and IHC. ROC analysis confirmed the ability to predict chemotherapy outcomes. Prognosis was evaluated using Kaplan-Meier., Results: In advanced high-grade serous ovarian cancer, 8 CpGs (ITGB6:cg21105318, cg07896068, cg18437633; NCALD: cg27637873, cg26782361, cg16265707; LAMA3: cg20937934, cg13270625) remained hypermethylated in chemoresistant patients. The sensitivity, specificity and AUC of 8 CpGs (ITGB6:cg21105318, cg07896068, cg18437633; NCALD: cg27637873, cg26782361, cg16265707; LAMA3: cg20937934, cg13270625) methylation to predict chemotherapy sensitivity were 63.60-97.00%, 46.40-89.30% and 0.774-0.846. PFS of 6 candidate genes (ITGB6:cg21105318, cg07896068; NCALD: cg27637873, cg26782361, cg16265707; LAMA3: cg20937934) hypermethylation patients was significantly shorter. The expression of NCALD and LAMA3 in chemoresistant patients was lower than that of chemosensitive patients. Spearman analysis showed that NCALD and LAMA3 methylations were negatively correlated with their expression., Conclusions: As a new biomarker of chemotherapy sensitivity, hypermethylation of NCALD and LAMA3 is associated with poor PFS in advanced high-grade serous ovarian cancer. In the future, further research on NCALD and LAMA3 will be needed to provide guidance for clinical stratification of demethylation therapy., (© 2021. The Author(s).)

Background: We investigated the therapeutic effect of targeting extracellular vesicles (EVs) loaded with indocyanine green (ICG) and paclitaxel (PTX) on glioma., Methods: Raw264.7 cells were harvested to extract EVs for the preparation of ICG/PTX@RGE-EV by electroporation and click chemistry. We evaluated the success of modifying Neuropilin-1 targeting peptide (RGE) on the EV membrane of ICG/PTX@RGE-EV using super-resolution fluorescence microscopy and flow cytometry. Spectrophotometry and high performance liquid chromatography (HPLC) were implemented for qualitative and quantitative analysis of the ICG and PTX loaded in EVs. Photothermal properties of the vesicles were evaluated by exposing to 808-nm laser light. Western blot analysis, cell counting kit 8 (CCK-8), Calcein Acetoxymethyl Ester/propidium iodide (Calcein-AM/PI) staining, and flow cytometry were utilized for assessing effects of vesicle treatment on cellular behaviors. A nude mouse model bearing glioma was established to test the targeting ability and anti-tumor action of ICG/PTX@RGE-EV in vivo., Results: Under exposure to 808-nm laser light, ICG/PTX@RGE-EV showed good photothermal properties and promotion of PTX release from EVs. ICG/PTX@RGE-EV effectively targeted U251 cells, with activation of the Caspase-3 pathway and elevated apoptosis in U251 cells through chemotherapy combined with hyperthermia. The anti-tumor function of ICG/PTX@RGE-EV was confirmed in the glioma mice via increased accumulation of PTX in the ICG/PTX@RGE-EV group and an increased median survival of 48 days in the ICG/PTX@RGE-EV group as compared to 25 days in the PBS group., Conclusion: ICG/PTX@RGE-EV might actively target glioma to repress tumor growth by accelerating glioma cell apoptosis through combined chemotherapy-hyperthermia., (© 2021. The Author(s).)

Background: Campylobacter fetus is an uncommon Campylobacter species, and its infections mainly cause infective endocarditis, aortic aneurysm, and meningitis rather than enteritis. It is more likely to be detected in blood than Campylobacter jejuni or Campylobacter coli, specifically reported in 53% of patients. In our case, C. fetus was detected in both blood and cerebrospinal fluid (CSF) cultures., Case Presentation: A 33-year-old woman, who was on maintenance chemotherapy for acute lymphoblastic leukemia (ALL), presented to our clinic with chief complaints of severe headache and nausea. Blood and CSF cultures revealed C. fetus. We administrated meropenem 2 g intravenously (IV) every 8 h for 3 weeks, and she was discharged without neurological sequelae., Conclusion: We encountered a case of C. fetus meningitis without gastrointestinal symptoms, neck stiffness or jolt accentuation in a patient with ALL. Undercooked beef was considered the source of C. fetus infection in this case, suggesting that the need for a neutropenic diet and safe food handling be considered., (© 2021. The Author(s).)

Purpose: To uncover the experience of time in women undergoing chemotherapy for ovarian cancer., Methods: A combination of consensual qualitative research and Giorgi's descriptive phenomenology., Results: The key phenomenon found and pre-reflectively organizing the patients' experience was the temporal paradox of chemotherapy-a sense of both acceleration and deceleration in between chemotherapy sessions that desynchronizes patients with the time of others., Conclusion: The experienced paradoxes concentrating around the timings of the chemotherapy treatments are of particular relevance for supportive care. It is particularly important to acknowledge the disturbing effect of the cyclical nature of chemotherapy.