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Among the different chemotherapies available, genotoxic drugs are widely used. In response to these drugs, particularly doxorubicin, tumor cells can enter into senescence. Chemotherapy‑induced senescence (CIS) is a complex response. Long described as a definitive arrest of cell proliferation, the present authors and various groups have shown that this state may not be complete and could allow certain cells to reproliferate. The mechanism could be due to the activation of new signaling pathways. In the laboratory, the proteins involved in these pathways and triggering cell proliferation were studied. The present study determined a new role for anterior gradient protein 2 (AGR2) in vivo in patients and in vitro in a senescence escape model. AGR2's implication in breast cancer patients and proliferation of senescent cells was assessed based on a SWATH‑MS proteomic study of patients' samples and RNA interference technology on cell lines. First, AGR2 was identified and it was found that its concentration is higher in the serum of patients with breast cancer and that this high concentration is associated with metastasis occurrence. An inverse correlation between intratumoral AGR2 expression and the senescence marker p16 was also observed. This observation led to the study of the role of AGR2 in the CIS escape model. In this model, it was found that AGR2 is overexpressed in cells during senescence escape and that its loss considerably reduces this phenomenon. Furthermore, it was shown that the extracellular form of AGR2 stimulated the reproliferation of senescent cells. The power of proteomic analysis based on the SWATH‑MS approach allowed the present study to highlight the mammalian target of rapamycin (mTOR)/AKT signaling pathway in the senescence escape mechanism mediated by AGR2. Analysis of the two signaling pathways revealed that AGR2 modulated RICTOR and AKT phosphorylation. All these results showed that AGR2 expression in sera and tumors of breast cancer patients is a marker of tumor progression and metastasis occurrence. They also showed that its overexpression regulates CIS escape via activation of the mTOR/AKT signaling pathway.

Introduction: Colorectal cancer is one of the most common malignant tumors and has a relatively poor prognosis. Lymph node involvement is considered the most important prognostic factor., Materials and Methods: During a retrospective cohort study, 132 patients with locally advanced rectal cancer who underwent neoadjuvant chemoradiotherapy followed by surgery for resectable rectal cancer from 2010 to 2015 in Sina hospital were reviewed., Results: Multivariable analysis was performed and shown the clinical stage was not a representative factor for disease-free survival (P = 0.187), but Dworak Tumor Regression Grading were significantly associated with higher disease-free survival (P = 0.000) in stage II and stage III. The total number of retrieved lymph nodes and involved lymph nodes in the same clinical stage were statistically associated with higher mean disease-free survival in patients (P = 0.000 in both conditions)., Conclusion: In the same clinical stage, increasing the Dworak Tumor Regression Grading reduced the risk of rectal cancer recurrence. Increasing total number of retrieved lymph nodes and involved lymph nodes, 2.14 times and 3.87 times increased the risk of recurrence, respectively., Competing Interests: None

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.)

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.)

The human body harbors a diverse microbiome that regulates host physiology and disease development. Several studies have also been reported where the human microbiome interferes with the efficacy of chemotherapeutics. Reports have also suggested the use of microbes in specific targeting and drug delivery. This review mainly focuses on the alteration in the efficacy of the drug by human microbiota. We have also discussed how the diversity in microbes can determine the therapeutic outcomes of a particular drug. The pathways involved in the alteration are also focused, with some highlights on microbes being used in cancer therapy., (© The Author(s) 2021. Published by Oxford University Press on behalf of FEMS. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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

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: Metronomic chemotherapy (MC) strategy has been used in breast cancer for more than a decade since it was first proposed. The purpose of this study is to systematically evaluate its efficacy and safety for breast cancer patients at various stages, as well as to clarify the most effective medication strategy when applying MC and discover its most sensitive subpopulation in breast cancer patients., Method: We will systematically retrieve random controlled trials evaluating the efficacy and safety of MC in breast cancer on PubMed, Cochrane Library, Embase, and web of science to perform this network meta-analysis. Markov chain Monte Carlo method based on Bayesian Theory will be used to conduct network meta-analysis and the efficacy and safety will be ranked by combining direct and indirect evidence in mixed treatment comparisons. We will assess the quality of literatures with the Cochrane Risk Bias Assessment Tool and assess the strength of the evidence using the GRADE methodology. Data analysis will be completed with the WinBUGS, R, Stata and RevMan softwares., Results and Conclusion: Through the analysis, we can obtain the ranking of efficacy and safety in different MC strategy, and reveal the specific breast cancer groups that are more sensitive to MC. We access the effectiveness by disease free survival, progress free survival, time to progress, objective response rate, and overall survival, and measure the toxicity by dose-limiting toxicity. The result of our study could provide evidence for clinicians to make a better choice when they consider MC., Inplasy Registration Number: INPLASY202140142., 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 aimed to compare the functioning, symptoms, and quality of life (QoL) of patients with breast or colon cancer before and after their first-cycle (FC) chemotherapy., Design: One-group pretest/posttest design., Method: The study utilized the standardized Arabic-translated Quality of Life Questionnaire Version 3 from the European Organization for Research and Treatment of Cancer in measuring the functioning, symptoms, and QoL of 120 Saudi patients diagnosed with breast or colon cancer. Dependent t test was used in analyzing the presence of significant differences in mean scores before and after chemotherapy with periods ranging from 14 days to 21 days following the treatment protocol., Results: The findings revealed significant differences in the functioning, symptoms, and QoL among patients with breast or colon cancer before and after FC chemotherapy ( p < .001). Baseline scores showed higher physical, role, emotional, cognitive, and social functioning; lesser symptoms; lower financial difficulties; and better overall global health status compared to post-FC chemotherapy., Conclusion: Assessing the QoL of patients with breast or colon cancer undergoing FC chemotherapy is essential to establish a holistic care plan in supporting and alleviating the unfavorable effects of chemotherapy and implement patient-centered interventions that aid in the enhancement of their overall QoL.

Background: It is important to assess the burden of chronic urticaria (CU) with real-life studies. The AWARE study was performed in 36 countries over two years in CU patients resistant to H1-antihistamines., Objectives: To correlate patient-reported outcomes and available therapeutic options in CU patients., Materials & Methods: The AWARE study was a prospective, non-interventional, international study that included adult patients who have had H1-antihistamine-resistant CU for at least two months. The primary endpoints were the evolution of disease activity (UAS7), urticaria control (UCT), dermatological quality of life (DLQI) and treatment satisfaction (visual analogic scale) during a two-year follow-up. The data from French centres are reported., Results: Ninety-two patients were included (mean age: 47.8 years; women: 70.7%; mean disease duration: 6.5 years; angioedema: 34.1%). The percentage of patients with CU treatment increased from 56.5% at inclusion to 86.0% after two years (for patients with non-sedative H1-antihistamines from 52.2% to 74.4%, and omalizumab from 2.2% to 25.6%). During the follow-up, the percentage of patients with UAS7 score <6 increased from 12.5% to 60.9%, and patients with well-controlled CU (UCT score >12) increased from 11.1% to 62.2%. The negative impact on quality of life (DLQI >10) decreased from 34.1% to 10.5%. The mean score of patient satisfaction for treatment increased from 4.6 to 7.6., Conclusion: The management of CU patients resistant to H1-antihistamines was not optimal at inclusion with uncontrolled disease, impaired quality of life and insufficient treatment. After a two-year follow-up, disease symptoms and quality of life improved, but the therapeutic management could be further optimized.

Standard treatment for classical Hodgkin lymphoma (cHL) is poorly tolerated in older patients and results disappointing. We assessed safety and efficacy of brentuximab vedotin (BV), in previously untreated patients with cHL unfit for standard treatment due to age, frailty or comorbidity. The primary outcome was complete metabolic response (CMR) by positron emission tomography/computed tomography after four BV cycles (PET4). The secondary outcomes included progression-free survival (PFS), overall survival (OS), and toxicity. In all, 35 patients with a median age of 77 years and median total Cumulative Illness Rating Scale for Geriatrics (CIRS-G) score of 6 were evaluable for toxicity and 31 for response. A median of four cycles were given (range one-16). In all, 14 patients required dose reduction due to toxicity and 11 patients stopped treatment due to adverse events (AEs). A total of 716 AEs were reported, of which 626 (88%) were Grade 1/2 and 27 (77%) patients had at least one AE Grade ≥3. At PET4, CMR was 25·8% [95% confidence interval (CI) 13·7-42.2%] and objective response rate 83·9% (95% CI 63·7-90·8%). Median PFS was 7·3 months (95% CI 5·2-9·0), and OS 19·5 months. Our results suggest that BV monotherapy is tolerable but suboptimal in the front-line therapy of elderly or comorbid patients with cHL. Combining BV with other agents may be more effective. Trial Registration: Clinicaltrials.gov identifier: NCT02567851., (© 2020 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: In cardiovascular disease, prevention strategies targeting standard modifiable cardiovascular risk factors (SMuRFs; hypertension, diabetes, hypercholesterolaemia, and smoking) are crucial; however, myocardial infarction in the absence of SMuRFs is not infrequent. The outcomes of individuals without SMuRFs are not well known., Methods: We retrospectively analysed adult patients with first-presentation ST-elevation myocardial infarction (STEMI) using data from the Swedish myocardial infarction registry SWEDEHEART. Clinical characteristics and outcomes of adult patients (age ≥18 years) with and without SMuRFs were examined overall and by sex. Patients with a known history of coronary artery disease were excluded. The primary outcome was all-cause mortality at 30 days after STEMI presentation. Secondary outcomes included cardiovascular mortality, heart failure, and myocardial infarction at30 days. Endpoints were also examined up to discharge, and to the end of a 12-year follow-up. Multivariable logistic regression models were used to compare in-hospital mortality, and Cox-proportional hazard models and Kaplan-Meier analysis for long-term outcomes., Findings: Between Jan 1, 2005, and May 25, 2018, 9228 (14·9%) of 62 048 patients with STEMI had no SMuRFs reaching diagnostic thresholds. Median age was similar between patients with SMuRFs and patients without SMuRFs (68 years [IQR 59-78]) vs 69 years [60-78], p<0·0001). SMuRF-less patients had a similar rate of percutaneous coronary intervention to those with at least one modifiable risk factor, but were significantly less likely to receive statins, angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockade (ARB), or β-blockers at discharge. By 30 days after presentation, all-cause mortality was significantly higher in SMuRF-less patients (hazard ratio 1·47 [95% CI 1·37-1·57], p<0·0001). SMuRF-less women had the highest 30-day mortality (381 [17·6%] of 2164), followed by women with SMuRFs (2032 [11·1%] of 18 220), SMuRF-less men (660 [9·3%] of 7064), and men with SMuRFs (2117 [6·1%] of 34 600). The increased risk of 30-day all-cause mortality in SMuRF-less patients remained significant after adjusting for age, sex, left ventricular ejection fraction, creatinine, and blood pressure, but was attenuated on inclusion of pharmacotherapy prescription (ACEI or ARB, β-blocker, or statin) at discharge. Additionally, SMuRF-less patients had a significantly higher rate of in-hospital all-cause mortality than patients with one or more SMuRF (883 [9·6%] vs 3411 [6·5%], p<0·0001). Myocardial infarction and heart failure at 30 days were lower in SMuRF-less patients. All-cause mortality remained increased in the SMuRF-less group for more than 8 years in men and up to the 12-year endpoint in women., Interpretation: Individuals who present with STEMI in the absence of SMuRFs have a significantly increased risk of all-cause mortality, compared with those with at least one SMuRF, which was particularly evident in women. The increased early mortality rates are attenuated after adjustment for use of guideline-indicated treatments, highlighting the need for evidence-based pharmacotherapy during the immediate post-infarct period irrespective of perceived low risk., Funding: Swedish Heart and Lung Foundation, National Health and Medical Research Council (Australia)., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Bevacizumab-combined chemotherapy is a new regimen for advanced/recurrent endometrial cancer., Aims: To evaluate the efficacy and safety of bevacizumab-combined chemotherapy in advanced/recurrent endometrial cancer., Study Design: Systematic review and meta-analysis., Methods: Eligible studies were retrieved from Embase, PubMed, and Cochrane Library. The data of primary outcomes including progression-free survival and overall survival and secondary outcomes including overall survival, response rate, and adverse events (grade ≥2) were extracted, pooled, and used for the meta-analysis to compare the efficacy and safety of bevacizumab-combined chemotherapy with other treatments in patients with advanced/recurrent endometrial cancer., Results: Notably, 2 randomized-controlled and 5 single-arm trials of bevacizumab-combined chemotherapy or bevacizumab single-agent therapy for endometrial cancer were included. Meta-analysis indicated that bevacizumab-combined chemotherapy significantly increased the progression-free survival rate (hazard ratio=0.82, 95% confidence interval=0.70, 0.97) and overall survival rate (hazard ratio=0.83, 95% confidence interval=0.70, 0.98) compared with chemotherapy alone. The rates of overall, complete, and partial response to bevacizumab-combined chemotherapy were 76%, 22%, and 21%, respectively. The 6 and 12-month disease-free progression rates after bevacizumab-combined chemotherapy were 79% and 62%, respectively. Anemia (23%), leukopenia (46%), neutropenia (51%), hypertension (16%), and fatigue (24%) were the general adverse events after bevacizumab-combined chemotherapy., Conclusion: Bevacizumab-combined chemotherapy may have a higher efficacy in improving the overall and progression-free survival in patients with advanced/recurrent endometrial cancers compared with chemotherapy alone.

Though the Quality Use of Medicines (QUM) principles have withstood the test of time, there are a number of challenges health care professionals face in today's society. An updated QUM framework would better reflect the current challenges we face.

Rationale: Patients reporting high PD-L1 expression have shown to respond well to immunotherapy; however, some patients develop hyperprogressive disease upon initiation of immune checkpoint inhibitors. We report a patient with lung cancer and 100% PD-L1 expression who developed hyperprogressive disease while treated with pembrolizumab and responded well to salvage chemotherapy with carboplatin and pemetrexed., Patient Concerns: A 66-year-old African American female with 25-pack year smoking history, diabetes mellitus type 2, essential thrombocytosis, and a history of papillary thyroid carcinoma developed relapsed lung adenocarcinoma after 13 months of no evidence of disease., Diagnosis: Surveillance imagine showed subcarinal and hilar lymphadenopathy, which was confirmed as recurrent lung adenocarcinoma via bronchoscopy. In addition, a brain scan showed a 5 mm enhancing left insular lesion. PD-L1 was reported as 100% expression. Staging was reported as stage IVB TxN3M1c lung adenocarcinoma., Interventions: One fraction of radiation with a total dose of 20 Gray was delivered to the left insular lesion. The patient initiated pembrolizumab (200 mg) every 3 weeks. She was then treated with salvage chemotherapy consisting of carboplatin (AUC 5) and pemetrexed (500 mg/m) every 3 weeks for 3 cycles., Outcomes: The brain lesion resolved after the radiation therapy. The patient developed hyperprogression with a large pericardial effusion and right pleural effusion after 2 treatments of pembrolizumab. Her PD-L1 expression decreased from 100% to 0% over a 10-week period. Salvage chemotherapy with carboplatin and pemetrexed resulted with 20 months of ongoing to evidence of disease., Lessons: Immune checkpoint inhibitor-related hyperprogressive disease may respond to second-line salvage chemotherapy. Complete PD-L1 expression loss was observed after the patient's treatment and could be a marker of hyperprogressive disease or tumor immunoevasion.

Background: The literature contains limited information on the problems faced by dying patients with COVID-19 and the effectiveness of interventions to manage these., Aim: The aim of this audit was to assess the utility of our end-of-life care plan, and specifically the effectiveness of our standardised end-of-life care treatment algorithms, in dying patients with COVID-19., Design: The audit primarily involved data extraction from the end-of-life care plan, which includes four hourly nursing (ward nurses) assessments of specific problems: patients with problems were managed according to standardised treatment algorithms, and the intervention was deemed to be effective if the problem was not present at subsequent assessments., Setting/participants: This audit was undertaken at a general hospital in England, covered the 8 weeks from 16 March to 11 May 2020 and included all inpatients with COVID-19 who had an end-of-life care plan (and died)., Results: Sixty-one patients met the audit criteria: the commonest problem was shortness of breath (57.5%), which was generally controlled with conservative doses of morphine (10-20 mg/24 h via a syringe pump). Cough and audible respiratory secretions were relatively uncommon. The second most common problem was agitation/delirium (55.5%), which was generally controlled with standard pharmacological interventions. The cumulative number of patients with shortness of breath, agitation and audible respiratory secretions increased over the last 72 h of life, but most patients were symptom controlled at the point of death., Conclusion: Patients dying of COVID-19 experience similar end-of-life problems to other groups of patients. Moreover, they generally respond to standard interventions for these end-of-life problems.

Importance: DNA repair gene aberrations occur in 20% to 30% of patients with castration-resistant prostate cancer (CRPC), and some of these aberrations have been associated with sensitivity to poly(ADP-ribose) polymerase (PARP) inhibition platinum-based treatments. However, previous trials assessing platinum-based treatments in patients with CRPC have mostly included a biomarker-unselected population; therefore, efficacy in these patients is unknown., Objective: To characterize the antitumor activity of platinum-based therapies in men with CRPC with or without DNA repair gene alterations., Design, Setting, and Participants: In this case series, data from 508 patients with CRPC treated with platinum-based therapy were collected from 25 academic centers from 12 countries worldwide. Patients were grouped by status of DNA repair gene aberrations (ie, cohort 1, present; cohort 2, not detected; and cohort 3, not tested). Data were collected from January 1986 to December 2018. Data analysis was performed in 2019, with data closure in April 2019., Exposure: Treatment with platinum-based compounds either as monotherapy or combination therapy., Main Outcomes and Measures: The primary end points were as follows: (1) antitumor activity of platinum-based therapy, defined as a decrease in prostate-specific antigen (PSA) level of at least 50% and/or radiological soft tissue response in patients with measurable disease and (2) the association of response with the presence or absence of DNA repair gene aberrations., Results: A total of 508 men with a median (range) age of 61 (27-88) years were included in this analysis. DNA repair gene aberrations were present in 80 patients (14.7%; cohort 1), absent in 98 (19.3%; cohort 2), and not tested in 330 (65.0%; cohort 3). Of 408 patients who received platinum-based combination therapy, 338 patients (82.8%) received docetaxel, paclitaxel, or etoposide, and 70 (17.2%) received platinum-based combination treatment with another partner. A PSA level decrease of at least 50% was seen in 33 patients (47.1%) in cohort 1 and 26 (36.1%) in cohort 2 (P = .20). In evaluable patients, soft tissue responses were documented in 28 of 58 patients (48.3%) in cohort 1 and 21 of 67 (31.3%) in cohort 2 (P = .07). In the subgroup of 44 patients with BRCA2 gene alterations, PSA level decreases of at least 50% were documented in 23 patients (63.9%) and soft tissue responses in 17 of 34 patients (50.0%) with evaluable disease. In cohort 3, PSA level decreases of at least 50% and soft tissue responses were documented in 81 of 284 patients (28.5%) and 38 of 185 patients (20.5%) with evaluable disease, respectively., Conclusions and Relevance: In this study, platinum-based treatment was associated with relevant antitumor activity in a biomarker-positive population of patients with advanced prostate cancer with DNA repair gene aberrations. The findings of this study suggest that platinum-based treatment may be considered an option for these patients.

Background: At present, the effect of western-medicine (WM) therapy to treat diabetic peripheral neuropathy (DPN) is limited. Moxibustion is a representative external treatment in traditional Chinese medicine that has been beneficial to DPN. We aim to systematically assess the efficacy and safety of moxibustion in treating DPN, following PRISMA guidelines., Methods: Eight electronic databases were searched to acquire information on eligible trials published from inception to June 1, 2019. We included randomized controlled trials (RCTs) applying moxibustion therapy with a minimum of 14-days treatment duration for DPN patients compared with placebo, no intervention, or conventional WM interventions. The primary outcomes in our study include the sensory-nerve conduction velocity (SNCV) and motor-nerve conduction velocity (MNCV). We used the Cochrane Collaboration Risk of Bias tool to assess the methodological quality of eligible RCTs. Statistical analyses were conducted using Review Manager 5.3. Risk ratios (RR) and mean differences (MD) were calculated with a 95% confidence interval (CI). The χ test was applied to assess the heterogeneity., Results: In total, 11 RCTs were included that involved 927 DPN patients. Compared with the control group, there was an increase in median MNCV (MD = 6.26, 95% CI 2.64-9.89, Z = 3.39, P = .0007) and peroneal MNCV (MD = 6.45, 95% CI 5.30-7.61, P < .00001). There was also an increase in median SNCV (MD = 6.64, 95% CI 3.25-10.03, P = .0001) and peroneal SNCV (MD = 3. 57, 95% CI 2.06-5.09, Z = 4.63, P < .00001) in the treatment groups. The treatment groups receiving moxibustion therapy indicated a more significant improvement in total effectiveness rate (RR = 0.25, 95% CI 0.18-0.37, Z = 7.16, P < .00001). Toronto Clinical Scoring System indicated a significant decrease in the treatment groups (MD = -2.12, 95% CI -2.82 to 1.43, P < .00001). Only 1 study reported that treatment groups experienced no adverse reactions. The other 10 studies did not mention adverse events., Conclusions: Moxibustion therapy may be an effective and safe option for DPN patients but needs to be verified in further rigorous studies.

Importance: Fluorouracil-based chemotherapy combined with anti-epidermal growth factor receptor/vascular endothelial growth factor therapy is the standard first-line treatment for metastatic colorectal cancer followed by low-intensity maintenance therapy to balance the clinical efficacy and adverse effects (AEs). However, there have been concerns about the AEs of capecitabine plus cetuximab as a maintenance therapy in patients with RAS wild-type metastatic colorectal cancer., Objective: To evaluate the biological activity and safety of capecitabine plus cetuximab as a novel maintenance therapy for RAS wild-type metastatic colorectal cancer., Design, Setting, and Participants: This phase 2 prospective clinical trial was conducted from April 29, 2016, to April 29, 2019, at 5 centers in China. Patients diagnosed as having RAS wild-type metastatic colorectal cancer were recruited to receive fluorouracil-based cytotoxic agents combined with cetuximab followed by capecitabine plus cetuximab for maintenance therapy. Forty-seven patients with histologically confirmed metastatic colorectal cancer and genetic test results showing a wild-type RAS were enrolled in maintenance therapy., Interventions: Induction therapy for patients with RAS wild-type metastatic colorectal cancer was 8 to 12 cycles of fluorouracil-based chemotherapy combined with cetuximab. After stable disease status or better was achieved, reduced-dose capecitabine plus cetuximab was administered for maintenance therapy., Main Outcomes and Measures: The primary end point was progression-free survival during maintenance therapy. The secondary end points were total progression-free survival, overall survival, quality of life, safety, and toxic effects of treatment., Results: Forty-seven patients were enrolled in maintenance therapy, with a median age of 52 years (range, 25-81 years) and 32 (68%) of them being men. The median maintenance progression-free survival was 7.2 (95% CI, 5.8-8.6) months. The median progression-free survival was 12.7 (95% CI, 11.8-15.4) months. The median overall survival was 27.4 (95% CI, 21.4-35.5) months. Grade 3 to 4 AEs during induction therapy included neutropenia (4 patients [9%]), diarrhea (4 patients [9%]), nausea or vomiting (3 patients [6%]), rash acneiform (10 patients [21%]), and hand-foot syndrome (8 patients [17%]). Grade 3 to 4 AEs during maintenance therapy included diarrhea (2 patients [4%]), rash acneiform (8 patients [17%]), and hand-foot syndrome (5 patients [11%])., Conclusions and Relevance: Reduced-dose capecitabine plus cetuximab after initial chemotherapy is a novel maintenance therapy for patients with RAS wild-type metastatic colorectal cancer that achieved good outcomes and tolerable nonserious AEs., Trial Registration: ClinicalTrials.gov Identifier: NCT02717923.

Irritable Bowel Syndrome (IBS), characterized by abdominal pain and bowel dysfunction, treatment focuses on alleviating symptoms. Adherence is crucial for pharmacologic management success. We examined 73 adult's objective adherence to rifaximin using the taxonomy for adherence. Demographic, quality of life (QOL), psychological distress, perceived stress, adverse childhood experiences (ACE), pain, and adherence data were collected. Impaired QOL, elevated psychological distress and perceived stress, and a significant number of ACE were reported at baseline. Average time to prescription initiation was 2.5 days. Once implemented, 92% missed midday dose and persisted 5 days beyond the prescribed dose. High-adherers reported lower pain levels post-rifaximin compared to low-adherers. Objective adherence was significantly lower than self-reported. Objective adherence was not predicted by above variables. Adherence to rifaximin is poor in those with IBS. Future research examining perceived barriers/facilitators toward rifaximin adherence may provide insight into patient-centered, modifiable targets for adherence interventions and improve patient-related outcomes.

Introduction: Metastatic neuroblastoma (NB) is an aggressive malignancy with a poor prognosis. Many patients present with relapsed high-risk NB after undergoing first-line treatment, and there is no standard therapy available in this setting., Patient Concerns: The present study aimed to present the cases of 2 patients with recurrent high-risk NB., Diagnosis: Two children with International Neuroblastoma Stage System stage 4 high-risk NB chemotherapy. The disease recurrent after finishing the treatment., Interventions: Both patients (34 months old and 41 months old) experienced recurrence, received second-line treatment, and then received maintenance treatment using apatinib plus retinoic acid. The apatinib (10 mg/kg per day) and retinoic acid (160 mg/m per day) were administered on alternating 2-week cycles, which was continued for 1 year., Outcomes: The 2 patients had achieved complete response by the 1-year follow-up after starting apatinib plus retinoic acid, and did not experience any adverse drug reactions., Conclusion: The outcomes from these cases suggest that apatinib plus isotretinoin might be an option for maintenance therapy in patients with recurrent high-risk NB.

Type 2 coronavirus pandemics that is plaguing almost all the world has caused  qualitative and quantitative strains in health systems that have had to be responded to. The lack of known vaccines and effective treatments has generated the need to  use drugs with very little evidence for their incorporation into pharmacotherapeutic  protocols agreed by the clinical team. The hospital pharmacist, within the  multidisciplinary team, has been responsible for critically evaluating the alternatives and positioning them in these protocols. Finally, some ethical and legal questions  that should be considered in this scenario are analyzed in this article., (Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.)

Introduction: Sex-based medicine, which can be defined as the process of understanding the inherent differences in disease pathophysiology and response to medications that exist between the sexes, seems like a necessary step in the movement towards personalized medicine. While there are strict guidelines for weight-based dosage of pediatric medications, similar guidelines do not exist for the treatment of adults, despite prominent biologic differences between the sexes. The lack of individualization is of particular importance in the treatment of adult patients in the emergency department (ED), because it can determine the trajectory of a patient's stay at the hospital., Objectives: This review was conducted to better understand the need for and possible benefits of altering drug dosing guidelines for different categories of medications in the ED. PubMed, SCOPUS, and Google Scholar were queried using a combination of the keywords "gender differences," "sex differences," "treatment," and "emergency". Abstracts, unpublished data, and duplicate articles were excluded., Discussion: In considering some of the most common causes of ED visits, the majority of diseases demonstrate differences in morbidity and mortality between female and male patients, despite similar treatment regimens. These differences can be attributed to variations in drug pharmacodynamics and pharmacokinetics, which may be affected by sex-based biologic variations in body mass index and body composition, and physiologic variations such as hormonal changes, menstruation, pregnancy, and lactation. Regardless of the mechanism of these differences, there is overwhelming evidence that universal drug dosing results in suboptimal outcomes for both male and female patients., Conclusions: Female sex is a risk factor for clinically significant adverse drug reactions, which range from cutaneous reactions to major bleeding, and can have long-standing implications on patient outcomes. However, future studies are needed to understand the exact pathophysiology of these sex differences, after controlling for potential confounding factors such as demographic differences and provider bias in treatment., Competing Interests: Declaration of competing interest The authors do not have a financial interest or relationship to disclose regarding this research project., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Good dispensing practice is vital for rational use of medicines. There are many paediatric specific challenges when maintaining good dispensing practices to children. Lack of age appropriate dosage forms, lack of medicines in strengths suitable for children, lack of palatable medicines, lack of expertise in paediatric pharmacy are few challenges faced when maintaining good dispensing practices to children. These challenges contribute to poor dispensing practices. Hence there is an urgent need to investigate whether oral dosage forms of medicines are dispensed rationally to children. The objective of this study was to describe the rational dispensing practice of oral dosage forms of medicines to children in a Teaching Hospital in Sri Lanka., Methods: A descriptive cross sectional study was conducted to assess the dispensing practice of 1800 oral dosage forms of medicines dispensed to children under the age of 12 years in two outdoor pharmacies over a period of 1 year using validated indicators. Required data were extracted from the prescriptions and by observation using a structured pre-tested observation sheet. Descriptive statistics and wherever relevant, chi square test were used in analysing the data., Results: Information on 1800 oral dosage forms was obtained from 1889 medicines dispensed to 727 children. Liquids were 52% [95% CI: 50-55%] of these oral dosage forms. Of the solid dosage forms, about one quarter required manipulation prior to administration such as splitting and dissolving or crushing the adult dosage form. None of the medicine packs or bottles had the patient name on the label., Conclusion: Dispensing practice of oral dosage forms of medicines to children has room for improvement.

X-linked hypophosphataemia (XLH) rickets is a rare disease frequently misdiagnosed and mismanaged. Despite having clinical guidelines that offers some therapeutic recommendations based on the clinical experience of experts, physicians still have questions about some important aspects of the diagnosis and treatment of XLH, such as when the disease should be suspected, who should be in charge of the diagnosis, what should be done once the disease is diagnosed, or what therapeutic options are currently available. The objective of this paper is to answer some of the more frequent questions related to the management of patients with XLH by a group of experts participating in a scientific conference on XLH held in Madrid.

Background and Aim of the Work: The main objectives of our work were the regional harmonization and standardization of pharmaceutical supplies on MSA in Lombardy., Methods: The retrospective investigation was articulated in 2 phases: the first was the collection of data in every area of the Region (2012), the second was the analysis and elaboration of the information retrieved., Results: Beginning with 24 common drugs used by 8 AATs out of 12 an evaluation of the chemical-therapeutic characteristics was performed. The temporary list, including over 80 drugs classified in more than 25 therapeutic groups, was finally reduced to provide bags that were easier to handle but at the same time complete. Between October and November 2014, the proposed supply, including 71 formulations and approved by the Technical Board of AREU, officially entered into force. At the same time, the working group followed the same procedure to define the standard equipment for the Region's helicopters, with only 58 formulations for relatively reduced weight allowed on board., Conclusions: In conclusion, we can state that, thanks to the support of experts, of the literature review, and thanks to the practical experience of the members of the AREU working groups and thanks to the documents coming from AIFA and EMA, the first operative regional project of unified pharmacological supply for MSA was delivered.

Despite advances in the field of pharmacogenetics (PGx), clinical acceptance has remained limited. The Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate PGx implementation by developing evidence-based pharmacogenetics guidelines to optimize pharmacotherapy. This guideline describes the starting dose optimization of three anti-cancer drugs (fluoropyrimidines: 5-fluorouracil, capecitabine and tegafur) to decrease the risk of severe, potentially fatal, toxicity (such as diarrhoea, hand-foot syndrome, mucositis or myelosuppression). Dihydropyrimidine dehydrogenase (DPD, encoded by the DPYD gene) enzyme deficiency increases risk of fluoropyrimidine-induced toxicity. The DPYD-gene activity score, determined by four DPYD variants, predicts DPD activity and can be used to optimize an individual's starting dose. The gene activity score ranges from 0 (no DPD activity) to 2 (normal DPD activity). In case it is not possible to calculate the gene activity score based on DPYD genotype, we recommend to determine the DPD activity and adjust the initial dose based on available data. For patients initiating 5-fluorouracil or capecitabine: subjects with a gene activity score of 0 are recommended to avoid systemic and cutaneous 5-fluorouracil or capecitabine; subjects with a gene activity score of 1 or 1.5 are recommended to initiate therapy with 50% the standard dose of 5-fluorouracil or capecitabine. For subjects initiating tegafur: subjects with a gene activity score of 0, 1 or 1.5 are recommended to avoid tegafur. Subjects with a gene activity score of 2 (reference) should receive a standard dose. Based on the DPWG clinical implication score, DPYD genotyping is considered "essential", therefore directing DPYD testing prior to initiating fluoropyrimidines.

Objectives: Oral treatment (targeted or chemotherapy) for cancer is being increasingly used. While fatigue is a known side effect of intravenous chemotherapy, the rate of fatigue and the impact of fatigue on other patient-reported outcomes are not well described., Method: At Massachusetts General Hospital Cancer Center, 180 adult patients prescribed oral targeted or chemotherapy for various malignancies enrolled in a randomized controlled trial of adherence and symptom management. Patients completed baseline self-reported measures of fatigue (Brief Fatigue Inventory; BFI), anxiety and depressive symptoms (Hospital Anxiety and Depression Scale; HADS), and quality of life, including subscales for physical, social, emotional, and functional well-being ([QOL] Functional Assessment of Cancer Therapy - General; FACT-G). We examined clinically relevant fatigue using a validated cut-off score for moderate-severe fatigue (BFI global fatigue ≥4) and tested the associations with anxiety symptoms, depressive symptoms, and QOL with independent samples t-tests., Results: At baseline, 45 of 180 participants (25.0%) reported moderate-severe fatigue. Fatigued patients experienced more anxiety symptoms (mean diff. 3.73, P < 0.001), more depressive symptoms (mean diff. 4.14, P < 0.001), and worse QOL on the total FACT-G score (mean diff. -19.58, P < 0.001) and all subscales of the FACT-G compared to patients without moderate-severe fatigue., Significance of Results: One in four patients on oral treatment for cancer experienced clinically relevant fatigue that is associated with greater anxiety and depressive symptoms and worse QOL.

Summary: Background. Interruptions occurring during the drug preparation and administration have a documented effect on patients' safety. However, literature has paid little attention to show how the introduction of a set of standardized organizational interventions, based on the combination of the current evidence, could reduce the number of interruptions occurring during drug therapy management. For this reason, this study used the most recent evidence to combine a set of standardized organizational interventions, and it was aimed to assess the effect of those interventions on the number of interruptions occurring during drug therapy management (Hypothesis a) and the overall duration of the therapy administration (Hypothesis b). Methods. A quasi-experimental study was performed, using pre- and a post- organizational implementation data collections in a single Italian center. The data collections were related to the interruptions and 40 shifts were randomly selected for both pre- and post-phase, respectively on December 2016 and February 2017. The standardized organizational interventions were implemented using the current evidence on this topic. Results. The standardized organizational interventions decreased the interruptions in the post-implementation phase, but those had not an effect on the duration of the therapy administration. Conclusions. This study represented an updated evidence, which describes the effect of a standardized and evidence-based set of organisational interventions' implementation on drug therapy management. Our results suggest a number of hints for managers and future researches. Managers should keep into account the usefulness of those interventions, while future researches with experimental designs are needed to provide harder evidence on this topic., Competing Interests: The authors of this article have no conflict of interests to disclose., (Copyright© by GIMLE.)

Purpose: Childhood cancer invades the child's daily life and has a strong influence on their living conditions and lifestyle. The treatment is an unpleasant experience and the children often perceive the treatment as worse than the actual disease. The aim of the present study was thus to explore the process of how healthcare professionals improved care for children undergoing sedation for intrathecal chemotherapy., Method: A constructivist grounded theory approach was applied and qualitative interviews with paediatricians (n = 2), anaesthetists (n = 2), paediatric nurses (n = 3) and nurse anaesthetists (n = 5)., Results: The theory of creating a shielding place emerged and conceptualized the pattern of behavior of healthcare professionals throughout the procedure of sedation for intrathecal chemotherapy for pediatric leukaemia. The theory explains the core category 'shielding' and the process of how healthcare professionals developed strategies to resolve their main concern: a striving to reduce discomfort and suffering induced by the procedure and the treatment. These strategies, used throughout the procedure, were; de-dramatizing, de-exposing and minimizing trespassing., Conclusions: The theory of creating a shielding place offers a greater understanding of how healthcare professionals included the child's perspective in their work and thereby enabled a more sensitive and supportive care that had an impact on both quality of care and patient safety. The results from the study contributes with theoretical knowledge that can be used for developing evidence-based care guidelines for the procedure of sedating a child with leukaemia for intrathecal chemotherapy., Competing Interests: Declaration of competing interest No conflict of interest has been declared by the authors., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Introduction: Extant literature lack studies on behavioural training or pharmacotherapy in Indian preschool children. With adverse long term outcomes, effective, safe and affordable early interventions for ADHD are a priority. Aim of this prospective study is to report on short term outcome of preschool ADHD with specific focus on safety and tolerability of medications., Methods: Children with ADHD aged 2.5-6 years were assessed for severity and adverse events at baseline and follow-up using Conner's abbreviated rating scale and Clinical Global Impression-Severity scale. Children with Autism spectrum disorder and those with social quotient less than 50 were excluded. Statistical Analysis included descriptive statistics and Repeated measures ANOVA., Results: Of 56 children recruited, 33.93 %(N = 19) were on behavioural interventions alone, 66.07 %(N = 37) were on a combination of medication and behavioural intervention. All children received treatment according to standard care. The most prescribed drug was clonidine (44.64%), then risperidone (28.7%), methylphenidate (10.7%) and atomoxetine (10.7%). Medication choice was determined by affordability, availability and comorbidity profile. Sedation occurred in 24 % of children on clonidine. Atomoxetine was not well tolerated in 2 children. Methylphenidate was well tolerated. Irrespective of medication choice, all children showed significant improvement at 12 weeks (p < 0.001)., Conclusions: Choice of interventions is largely determined by availability and affordability. There is a need for structured parent behavioural training program deliverable in low resource setting. Anti-ADHD medications should be made available under the NMHP, RBSK program and all government settings in India, to address over-prescription of antipsychotics in preschool ADHD., Competing Interests: Declaration of Competing Interest None., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: Improvement of quality-of-life (QoL) has been termed as a primary objective in initiating therapy in both Parkinson's disease (PD) and multiple system atrophy Parkinsonian subtype (MSA-P). We aimed to compare the determinants of life quality in drug naïve PD and MSA-P patients., Methods: Eighty-six drug-naïve PD patients and thirty-five drug-naïve MSA-P patients were included to explore the determinants of QoL. Demographic information, motor deficits, and non-motor symptoms were included in the clinical assessment., Results: Both motor and non-motor functions were more severely impaired in the drug-naïve MSA-P patients, with higher PDQ-39 scores indicating poorer QoL. Physical discomfort and stigma were the main affected sub-domains in PD, while mobility and activity of daily life were the main affected ones in MSA-P. BECK depressive scores and UPDRS-III scores were independent variables of PDQ-39 in MSA-P patients. Age, depression, disease stages and non-motor scores were independent variables of PDQ-39 in PD patients., Interpretation: Drug-naïve MSA-P patients suffered from more severe motor and non-motor disability, as well as poorer QoL. Depression and non-motor symptoms were proved to be the most critical determinants for QoL in PD, while motor function was supposed to be the major determinant for MSA-P. When initiating therapy, physicians need to focus more on motor functions in drug-naïve MSA-P patients, but on depression in PD patients.

Medication use in pregnancy is common, but information about the safety of most medications in pregnant women or their infants is limited. In the absence of data from randomized clinical trials to guide decisions made by regulators, clinicians, and patients, we often have to rely on well-designed observational studies to generate valid evidence about the benefits and risks of medications in pregnancy. Spontaneous reporting, primary case-control and cohort studies, pregnancy exposure registries, and electronic health data have been used extensively for studying medication safety in pregnancy. This article discusses these data sources, their strengths and limitations, and possible strategies and approaches to mitigating limitations when planning studies or interpreting findings from the literature. Strategies discussed include combining data sources across institutional or national borders, developing and using more sophisticated study designs, and taking advantage of existing analytic methods for more complex data structures, such as time-varying exposure or unmeasured confounding. Finally, we make recommendations for study designs that aid in better risk-related communication., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background and Objectives: Evaluation of data from electronic health care records could help in guiding towards more rational drug treatments. This single center study evaluated clinical characteristics that could be associated with disease progression. Methods: This was a real world data (RWD) study using existing data from the registries of a university hospital. Patients had lung adenocarcinoma and they had received 1st line treatment. Treatment patterns and survival parameters were characterized and clinical characteristics of the patients were evaluated together with their association with disease progression. Results: 80 stage III/IV patients fulfilling inclusion criteria were identified. Mean age was 62 years and 61% were men. In total, 65% were current smokers and 82% had performance status (ECOG) 0/1. Median progression free survival (mPFS) and median overall survival (mOS) for stage III and IV patients were 8.5 and 5.4 months, and 21.9 and 8.6 months, respectively. The study found that 69% of patients progressed within 9 months from the start of the 1st line treatment. Poor performance status (ECOG 3), male gender, and smoking suggested faster disease progression. Most had received cis/carboplatin-based treatment in the 1st line. Cisplatin regimens were associated with more complete responses and better PFS and OS than the carboplatin ones. Conclusions: By combining algorithmic and manual validation of electronic health care records, clinically valid characteristics and outcomes could be evaluated and presented. This approach forms a basis for tools such as quality registries that can guide treatment decisions.

Hidradenitis suppurativa is a chronic folliculitis affecting intertriginous areas. Onset generally occurs in young adulthood to middle adulthood (18 to 39 years of age). Females and blacks are more than twice as likely to be affected. Additional risk factors include family history, smoking, and obesity. Hidradenitis suppurativa is associated with several comorbidities, including diabetes mellitus and Crohn disease. The clinical presentation of hidradenitis suppurativa ranges from rare, mild inflammatory nodules to widespread abscesses, sinus tracts, and scarring. Quality of life is often affected, and patients should be screened for depression. Treatment includes wearing loose-fitting clothes, losing weight if overweight, and smoking cessation. Topical clindamycin alone can be effective for patients with mild disease. Patients with moderate disease can be treated with oral antibiotics, such as tetracyclines, in addition to topical clindamycin. Adalimumab, a tumor necrosis factor alpha inhibitor, is effective for patients with moderate to severe hidradenitis suppurativa. Surgical procedures are often necessary for definitive treatment and include local procedures, such as punch debridement and unroofing/deroofing. Wide excision is indicated for patients with severe, extensive disease and scarring.

Understanding how countries review their national standard treatment guidelines (STGs) and essential medicines list (EML) is important in the light of ever-changing trends in public health and evidence supporting the selection and use of medicines in disease management. This study examines the 2017 STGs and EML review process, the actors involved and how the list of medicines and disease conditions evolved between the last two editions. We examined expert committee reports, stakeholder engagement reports and the last two editions (2010, 2017) STGs and EML. The review process occurred in both bureaucratic and public arenas where various actors with varied power and interest engaged in ways to consolidate their influence with the use of evidence from research and practice. In the bureaucratic arena, a national medicines selection committee inaugurated by the Minister of Health assessed the 2010 edition through technical sessions considering the country's disease burden, hierarchical healthcare structure and evidence on safety and efficacy and expert opinion. To build consensus and ensure credibility service providers, professional bodies and healthcare managers scrutinized the assessed guidelines and medicines list in public arenas. In such public arenas, technical discussions moved towards negotiations with emphasis on practicability of the policies. Updates in the 2017 guidelines involved the addition of 64 new disease conditions in the STG, with the EML including 153 additional medicines and excluding 56 medicines previously found in the 2010 EML. Furthermore, the level of care categorization for Level 'A' [i.e. community-based health planning and services (CHPS)] and Level 'M' (i.e. midwifery and CHPS with a midwife) evolved to reflect the current primary healthcare and community mobilization activities for healthcare delivery in Ghana. Ghana's experience in using evidence from research and practice and engaging wide stakeholders can serve as lessons for other low and middle-income countries., (© The Author(s) 2019. Published by Oxford University Press in association with The London School of Hygiene and Tropical Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Surgery for retroperitoneal sarcomas should be "en bloc" compartmental, which involves resection of unaffected organs. Its upfront use is key, providing a high percentage of resections with negative margins, resulting in a better local control and increased survival in many patients. Preservation of organs should be done in an individualized manner, especially in the pelvic location, and adapted to the histological aggressiveness of the tumor. Preoperative biopsy is able to establish the diagnosis of sarcoma subtype and consequently an adequate perioperative strategy. These patients should be managed by expert surgeons at referral centers with multidisciplinary units and oncology committees. The use of chemotherapy and radiotherapy is not yet well defined, so it is only recommended at referral centers with clinical trials. Currently, this is the only option to offer the best morbidity and mortality rates, as well as possible improvements in the survival of these patients., (Copyright © 2019 AEC. Publicado por Elsevier España, S.L.U. All rights reserved.)

Objectives: The present study aims to evaluate existing policy and practice relating to the use of pharmacological treatments with patients suffering from paraphilic disorders who are at risk of committing further sexual offences. Methods: A systematic literature search was conducted to document current legal policies across 26 different countries. In addition, a questionnaire assessing the practice of pharmacological treatment was sent to practitioners involved in the treatment of patients with paraphilic disorders. Results: Legal policies concerning the preconditions of using pharmacological treatments differ considerably between countries, and for most jurisdictions do not exist. Drawing on the responses of 178 practitioners, pharmacological agents are a useful addition to psychotherapeutic interventions, especially with those patients classified as medium or high risk for sexually violent behaviours. It would appear that most patients are medically examined, are informed of the risks and possible side effects before treatment commences and are also obliged to sign a consent form. Conclusions: Although pharmacological agents can be seen as an intrusion into a patients' sexual self determination, results indicate that ethical and clinical standards are being met in the majority of cases. However, further promotion of current WFSBP treatment guidelines would help to standardise practice across North American and European countries.

Purpose: The most significant peer-reviewed articles pertaining to infectious diseases (ID) pharmacotherapy, as selected by panels of ID pharmacists, are summarized., Summary: Members of the Houston Infectious Diseases Network (HIDN) were asked to nominate peer-reviewed articles that they believed most contributed to the practice of ID pharmacotherapy in 2017, including the areas of human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS). A list of 33 articles related to general ID pharmacotherapy and 4 articles related to HIV/AIDS was compiled. A survey was distributed to members of the Society of Infectious Diseases Pharmacists (SIDP) for the purpose of selecting 10 articles believed to have made the most significant impact on general ID pharmacotherapy and the single significant publication related to HIV/AIDS. Of 524 SIDP members who responded, 221 (42%) and 95 (18%) members voted for general pharmacotherapy- and HIV/AIDS-related articles, respectively. The highest ranked articles are summarized below., Conclusion: Remaining informed on the most significant ID-related publications is a challenge when considering the large number of ID-related articles published annually. This review of significant publications in 2017 may aid in that effort.

Background: To improve drug treatment in older people, who often present with multimorbidity and related polypharmacy, the FORTA (Fit fOR The Aged) List was developed via a Delphi consensus procedure. As a patient-in-focus listing approach (PILA), it has been clinically validated (VALFORTA trial). Unlike drug-oriented listing approaches (DOLAs), its application requires knowledge of patients' characteristics, including diagnoses and other details. As a drug list with discrete labels, application of FORTA seems particularly amenable to electronic support., Methods: An information technology (IT) algorithm was developed to analyze bulk data on International Classification of Diseases (ICD)-coded diseases and Anatomical Therapeutic Chemical (ATC)-coded drugs. FORTA-labeled diagnoses and drugs were used to compute the FORTA score, an automatically generated score that describes medication quality by adding up points assigned for errors related to over- and under-treatment. The algorithm detects mismatches between diagnoses and drugs, suboptimal drugs, omitted drugs, and deficient medication escalation schemes. The read-out produces explanations for each error point., Results: A total of 5603 and 7954 patients ≥ 65 years were included from two claims datasets (> 30,000 patients each, public health insurance). The FORTA scores were comparable (mean ± standard deviation 4.29 ± 3.37 vs. 4.17 ± 3.16), and similar to that determined in VALFORTA (pre-intervention 3.5 ± 2.7). Under-treatment was two times more prevalent than over-treatment. The main areas of under-treatment were pain, type 2 diabetes mellitus, and depression, and the main areas of over-treatment were gastrointestinal (proton pump inhibitors), pain (non-steroidal anti-inflammatory drugs), and arterial hypertension (β-blockers). The FORTA score is positively correlated with higher age, a higher Charlson Comorbidity Index, and more frequent hospitalizations. Patients in disease management programs run by public health insurers had higher scores than comparators., Conclusions: The algorithm produces plausible analyses of medication errors in older people, pointing to established areas of therapeutic deficiencies. Though individual recommendations exist, the algorithm cannot employ the full potential of FORTA as important details (e.g., blood pressure values, pain intensity) are not (yet) included. However, it seems capable of detecting medication problems in large cohorts-FORTA-EPI (Epidemiological) is designed to support epidemiological analyses, e.g., on comparisons of large cohorts, interventional impact, or longitudinal trends.

Purpose: To summarize the top 10 most influential peer-reviewed infectious diseases (ID) pharmacotherapy articles published in the year 2018., Summary: Members of the Houston Infectious Diseases Network (HIDN) nominated articles that were thought to have most notably contributed to ID pharmacotherapy in 2018, including those related to human immunodeficiency virus (HIV). A total of 26 articles were nominated: 22 articles pertaining to general ID pharmacotherapy and 4 articles involving HIV/AIDS. To select the most significant articles of 2018, a survey was created and distributed to members of the Society of Infectious Diseases Pharmacists (SIDP) asking members to vote on their top 10 general ID publications and 1 HIV publication. Of the 462 members surveyed, 213 (46%) and 108 (23%) voted for general ID pharmacotherapy- and HIV-related articles, respectively. The top article(s) for both categories are summarized., Conclusion: With the increased emphasis on antimicrobial stewardship initiatives and the growing problem of multidrug-resistant (MDR) organisms, the amount of ID literature centered on stewardship, appropriate treatment durations, and newly approved antimicrobial agents continues to expand, making it challenging for clinicians to stay informed on the most relevant publications. This review summarizes significant ID-related publications in 2018 with the goal of aiding clinicians in staying up to date on the most noteworthy publications in ID pharmacotherapy.

Objective: Soft tissue sarcoma (STS) is a rare cancer type that when locally advanced or metastatic, is predominantly treated with palliative chemotherapy with the aim of improving both quantity and quality of life. Given modest survival data after commencing first line chemotherapy, this study examines (i) what constitutes health related quality of life (HRQoL), (ii) whether the most commonly used HRQoL assessment tool measures this and (iii) to what extent HRQoL, and its components, change during and after treatment., Design: Mixed-methods longitudinal study of 66 sarcoma patients living with STS (42 commencing chemotherapy, 24 under surveillance after completing chemotherapy) involving serial EORTC QLQ-C30 questionnaires and nested-qualitative semi-structured interviews with a sub-sample of participants. EORTC QLQ-C30 score change from baseline to primary evaluation point was examined using a paired t-test. Interviews were analysed using the framework approach before both datasets were integrated., Results: Five main factors, including control of pain, were identified by study participants as important components of HRQoL; these are examined within the EORTC QLQ-C30. However, others e.g. independence loss and common causes of anxiety, are not. Whilst social and psychological domains are addressed by the EORTC QLQ-C30, the quantitative change over time did reflect qualitative descriptions of decline. The mean overall EORTC QLQ-C30 HRQoL score deteriorated from baseline (60.4) to the primary evaluation point (50.2) [change of -10.2, t-test: -2.70, p = 0.01] for those receiving chemotherapy; this was in concordance with patients' qualitative accounts. Baseline overall HRQoL scores were higher in the surveillance group suggesting a correlation with chemotherapy response and longer-term improvement in HRQoL. The evidence from both HRQoL scores and qualitative accounts indicated that the presence and control of physical symptoms were particularly important in maintaining HRQoL. Whilst fatigue deteriorated on chemotherapy (baseline 41.7 to 52.8; change of +11.1, t-test +2.51, p<0.05), pain (baseline 41.5 to 32.1; change -9.4, t-test -2.06 p<0.05) and sleep disturbance (43.1 to 28.5; change -14.6, t-test -3.05, p<0.05) both improved., Conclusion: A key finding was that the EORTC QLQ-C30 assesses some but not all of the patient-reported components of HRQoL in sarcoma patients highlighting the need for either STS specific modules within the EORTC QLQ-C30 or a completely new STS specific HRQoL tool. First line palliative chemotherapy improves specific symptoms known to be prevalent and to influence HRQoL in this patient group which in some patients may translate to sustained improvement in HRQoL: further exploration and validation of these findings in larger prospective studies are warranted., Competing Interests: The authors have declared that no competing interests exist.