Affecting Treatment Response Research Articles

Single-cell trajectories of melanoma cell resistance to targeted treatment.

Objective:Cellular heterogeneity is regarded as a major factor affecting treatment response and resistance in malignant melanoma. Recent developments in single-cell sequencing technology have provided deeper insights into these mechanisms.Methods:Here, we analyzed a BRAFV600E-mutant melanoma cell line by single-cell RNA-seq under various conditions: cells sensitive to BRAF inhibition with BRAF inhibitor vemurafenib and cells resistant to BRAF inhibition with vemurafenib alone or vemurafenib in combination with the MEK1/2 inhibitors cobimetinib or trametinib. Dimensionality reduction by t-distributed stochastic neighbor embedding and self-organizing maps identified distinct trajectories of resistance development clearly separating the 4 treatment conditions in cell and gene state space.Results:Trajectories associated with resistance to single-agent treatment involved cell cycle, extracellular matrix, and de-differentiation programs. In contrast, shifts detected in double-resistant cells primarily affected translation and mitogen-activated protein kinase pathway reactivation, with a small subpopulation showing markers of pluripotency. These findings were validated in pseudotime analyses and RNA velocity measurements.Conclusions:The single-cell transcriptomic analyses reported here employed a spectrum of bioinformatics methods to identify mechanisms of melanoma resistance to single- and double-agent treatments. This study deepens our understanding of treatment-induced cellular reprogramming and plasticity in melanoma cells and identifies targets of potential relevance to the management of treatment resistance.

Managing Diabetic Macular Edema in Clinical Practice: Systematic Review and Meta-Analysis of Current Strategies and Treatment Options.

PurposeThis meta-analysis aims to summarize 12-month best-corrected visual acuity (BCVA) outcomes in response to anti-vascular endothelial growth factor (VEGF) therapy and dexamethasone implant for the treatment of diabetic macular edema (DME) and to identify factors affecting treatment response using evidence generated from meta-regression.MethodsA systematic review of electronic databases was conducted to identify randomized controlled trials (RCTs) and real-life/observational studies that reported 12-month changes in BCVA in patients with DME on anti-VEGF or dexamethasone implant treatment in monotherapy. Study factors that were analyzed are baseline patient characteristics, study type, drug employed, number of injections and 12-month change in BCVA. Data were pooled in a random-effects meta-analysis with BCVA change as the main outcome. Meta-regression was conducted to assess the impact of multiple covariates.ResultsOne-hundred-five heterogeneous study populations (45,032 eyes) were identified and included in the analysis. The use of anti-VEGFs and dexamethasone implant induced an overall increase of +8.13 ETDRS letters in BCVA at 12 months of follow-up. Meta-regression provided evidence that mean BCVA change using anti-VEGFs was not statistically higher for RCTs (p=0.35) compared to observational studies. Dexamethasone implant showed a trend for better results in observational studies over RCTs. Populations following a fixed aflibercept regimen performed better than those following a reactive treatment regimen. Mean BCVA gain was higher in younger populations (p<0.001), with lower baseline BCVA (p<0.0001) and longer diabetes duration (p<0.0001), receiving a higher number of injections (p<0.0001).ConclusionIntravitreal therapy with anti-VEGFs or dexamethasone implant produces a significant improvement in BCVA at 12 months in patients with DME. Meta-regression identified the modifiable covariates that can be targeted in order to maximize functional results.

Squaric acid dibutyl ester for the treatment of alopecia areata: A retrospective evaluation.

Squaric acid dibutyl ester (SADBE) as topical immunotherapy is a good alternative in patients with refractory alopecia areata. In this study, we aimed to evaluate the effectiveness of SADBE treatment in alopecia areata (AA) and alopecia totalis/alopecia universalis (AT/AU) patients and determine the prognostic factors affecting treatment response. Data obtained from 34 (AA/AT/AU) patients treated with SADBE were analyzed retrospectively. Of the 34 patients, 16 (47.1%) were female and 18 (52.9%) were male. Sufficient responses were obtained in 19 (55.9%) patients. About 9 of the 19 patients (47.4%) with sufficient response reached a cosmetically acceptable level. As the severity of disease subsided, response to treatment increased. A better response was obtained when the disease onset in the spring and winter. Patients with a disease duration between 1 and 5 years responded better to the SADBE treatment compared to those with a disease shorter than 1 year and longer than 5 years. Severity of the disease, onset season of the disease, number of flares, duration of disease, and low levels of vitamin D in adult patients were observed to affect the SADBE response negatively.

Evaluation of Clinical Properties and Treatment Responses of Infantile Hemangioma.

Infantile hemangiomas are the most common vascular tumors in childhood. Although spontaneous regression is common; several infantile hemangioma patients need treatment due to possible morbidities. The aim of this study was to investigate the medical methods used in the treatment of infantile hemangiomas and to evaluate the factors affecting treatment response. Clinical and demographic characteristics, risk factors, treatment indications, modalities, duration, and responses of 100 patients between January 2007 and January 2017 were evaluated. The most common form of hemangiomas was superficial lesions. Sixty three per cent of the patients were female. Ulceration and hemorrhage were found in 26% of the cases and ocular problems were detected in 3% of the cases. Among the indications for treatment were cosmetic reasons with 56%, ulcer and bleeding with 25% and risk of vision problems with 13%. Propranolol with/without steroid was used as first line treatment and response rates were: 84 patients with more than 50% response, 9 patients with less than 50% response and 7 patients with treatment refractory. The most important factor affecting the treatment response was age at the beginning of the treatment. Duration of treatment, presence of ulceration, location, and size of hemangioma were also found to have significant effects on responses. This study demonstrated the importance of the kind and initiation time of infantile hemangioma treatment. A strong positive effect can be reached by starting treatment before the end of the proliferation phase. J Drugs Dermatol. 2020;19(12): doi:10.36849/JDD.2020.5009.

Delivering HDAC over 3 or 5 days as consolidation in AML impacts health care resource consumption but not outcome

AbstractPostremission treatment is crucial to prevent relapse in acute myeloid leukemia (AML). High-dose cytarabine delivered every 12 hours on days 1, 3, and 5 (HDAC-135) is the standard of care for younger adult patients with AML. Although this standard has been unsuccessfully challenged by other treatment regimens, including multiagent chemotherapy, the timing of HDAC administration has attracted little attention. Here, we retrospectively compared the safety, efficacy, and health care resource consumption associated with HDAC-135 and another standard, condensed HDAC-123 regimen, as consolidation treatment in younger AML patients in first complete response. This study included 221 patients (median age, 46.6 years; range, 18-60 years). HDAC-123 and HDAC-135 were used in 92 and 129 patients, respectively. Both regimens were associated with similar rates of relapse-free survival, cumulative incidence of relapse, nonrelapse mortality, and overall survival, including in core binding factor AML subgroup in which levels of minimal residual disease reduction were similar in both schedules. Hematological recovery times regarding neutrophils and platelets were significantly shorter in patients receiving HDAC-123, with an average difference of 3 to 4 days for each consolidation cycle. The total duration of hospitalization for the whole postremission program was shorter with HDAC-123 (32 days; interquartile ratio [IQR], 22.0,36.5) compared with HDAC-135 (41 days; IQR, 30.5, 50.0) (P< .0001). In conclusion, the condensed HDAC-123 regimen induced faster hematological recovery and therefore significantly reduced the length of hospital stay without affecting treatment response or outcome in younger AML patients.

Abstract 1842: F10 and 5-fluorouracil: Chemotherapeutic potential of F10 in alleviating colon cancer racial health disparity

Abstract Colorectal cancer (CRC) is the second most lethal cancer in the United States, but underlying its incidence and mortality is a disproportionate burden in African Americans (AA). Compared to Caucasian Americans (CA), AA patients are 30% more likely to develop and 50% more likely to die from CRC. Socioeconomic factors contribute to racial health disparity. However, recent evidence suggests that biological factors may shape the AA patient predisposition. Clinical assessment has shown that AA CRC patients have a higher rate of chemoresistance, tumor recurrence post-resection, and lower 5-year survival rate post-resection as compared to CA CRC patients. 5-fluorouracil (5-FU) has been the standard of care against CRC for more than 50 years. However, high chemoresistance in AA patients has become apparent. Thus, the formulation of safer and more effective chemotherapeutic agents is paramount. Using the MTT proliferation assay, we evaluated the efficacy of the fluoropyrimidine polymer ‘F10' (a promising chemotherapeutic agent) against 3 novel AA CRC cell lines (SB501, SB521, and CHTN06) and compare its potential effectiveness against 5-FU. Additionally, we assessed the potential differential efficacy of F10 between the three novel AA CRC cell lines and three CA CRC cell lines (e.g., HT29 and a p53+/+ wild type and a p53-/- variant of HCT116). A high potency of F10 in inducing DNA-directed apoptosis was shown to be significant regardless of p53 status. Given that AA CRC patients have a higher rate of unique TP53 polymorphisms linked to chemoresponse and chemoresistance, this finding is important. In 4 out of 6 cell lines, the IC50 value significantly decreased for F10 as compared to 5-FU. HCT116 -/-, HCT116 +/+, HT29, and SB521 exhibited ~12-fold, ~150-fold, ~10-fold, and ~6850-fold decrease in IC50 value for F10 compared to 5-FU, respectively (Two-Sample T-Test: HCT116-/-: p = 0.0043, HCT116 +/+: p = 0.0483, HT29: p = 0.0386, SB521: p = 0.0122). The cell line with wild type p53 exhibited a strong benefit from F10. In general, cell lines with p53 mutations showed benefits, but to a lesser extent; suggesting that both p53-dependent and p53-independent mechanisms are responsible for F10 chemotherapeutic activity. In addition, RNAseq analysis of each cell line was assessed and differential expression compared. Several differences between and within racial cell lines were defined. Notably, in AA some of these were associated with drug absorption (e.g., SLC28A2 and CES1). Additionally, p53 mutations within the AA cell lines were identified. Identifying and understanding genetic variables affecting treatment response is critical in the development of effective chemotherapeutic agents. Overall, validation of F10 as a chemotherapeutic agent is needed to assist in the development of treatment modalities which are effective for all CRC patients regardless of race and ethnicity. Citation Format: Shrey Thaker, William H. Gmeiner, Ping Ji, Jovanny Zabaleta, Tiana Reyes, Matthew DiGiovanni, Xuefeng Wang, Jennie L. Williams. F10 and 5-fluorouracil: Chemotherapeutic potential of F10 in alleviating colon cancer racial health disparity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1842.

Retrospective Study of Dupilumab Treatment for Moderate to Severe Atopic Dermatitis in Korea: Efficacy and Safety of Dupilumab in Real-World Practice.

Among biological agents for the treatment of atopic dermatitis (AD), dupilumab is a front-runner. Although many studies have been conducted on the real-world use of dupilumab, the sample size is often small and data is primarily on Western people. Therefore, we investigated the efficacy and safety of dupilumab in patients with moderate-to-severe AD in Korea. All patients with moderate-to-severe AD treated with dupilumab from September 2018 to June 2019 in this institution were included and analyzed by medical records. They were evaluated using the Eczema Area and Severity Index (EASI), Numerical Rating Scale (NRS), Patient Oriented Eczema Measure (POEM), and Dermatology Quality of Life Index (DLQI), respectively on admission, after two weeks (only EASI and NRS) and after 16 weeks. Laboratory tests were measured before and 16 weeks after treatment. A total of 101 patients were included. All efficacy tools showed a significant decrease after 16 weeks; EASI 77.4%, NRS 70.0%, POEM 60.7%, and DLQI 65.0%. EASI was characterized by a marked improvement of 51.5% in just two weeks. The treatment response was not significantly different according to the interval of treatment. Elevated Lactate Dehydrogenase (LDH) at 16 weeks was associated with poor treatment response. Moreover, a high eosinophil count was related to a lower change in EASI and POEM. In the correlation analysis, EASI was not correlated to DLQI before treatment. For changes after 16 weeks, POEM showed the highest correlation with DLQI. (R = 0.66, p < 0.001) In the additional analysis for factors affecting treatment response, the female gender was associated with good treatment response. (odds ratio = 5.4, p = 0.04) Adverse events from treatment included facial erythema (9.9%) and conjunctivitis (5.0%). Overall, it was confirmed that the efficacy of dupilumab in the real-world is similar to that of the existing clinical trials. We suggest that POEM is a useful tool for identifying the quality of life. The female gender was associated with a good treatment response. Both an elevated LDH and a high eosinophil count could be a therapeutic biomarker. Further research will be needed for a long-term period.

Pulmoner Arteriyel Hipertansiyon Olgularının Özellikleri, Tedavi Yanıtına Ve Sağkalıma Etkili Faktörlerin Değerlendirilmesi

Pulmoner Arteriyel Hipertansiyon Olgularının Özellikleri, Tedavi Yanıtına Ve Sağkalıma Etkili Faktörlerin Değerlendirilmesi

Peripheral Blood Monocytes in Prediction of Response to Direct Acting Antiviral Drugs in Chronic HCV Patients

Background: Eradication rate of hepatitis C virus (HCV) infection had dramatically increased in era of direct acting antivirals (DAAs). However, predicting relapse post-treatment had to be more speculated. Aim: to evaluate role of peripheral blood monocytes (PBMCs) HCV PCR as predictor of post-treatment relapse. Methods: For chronic HCV patients who achieved end of treatment response, HCV PCR at PBMNs was assessed in relation to SVR. Results: 112 out of 118 cases had SVR 24 with only six relapsers (5.1%). Negativity of triple HCV RNA was significantly lower in relapsers than in patients who achieved SVR (16.7% versus 92.9%, p= 0.001). Cases with two positive strands were relapsers (n= 2,33.3%). Single RNA positive strand was detected in 50% of relapsers (n=3) and in 8 out of 112 (7.1%) of patients who achieved SVR. Significant factors affecting treatment response were absence of esophageal varices, negativity of triple HCV RNA, albumin, platelets, INR, creatinine and MELD score. On multivariate analysis, negativity of triple HCV RNA was significant predictor of achieving SVR with 208.38 Odds Ratio and 95% CI (4.93-8809.97, p= 0.005). Conclusion: Relying on presence of HCV on PBMCs at end of treatment with DAAs might be a trustworthy independent predictor of relapse.

Real-Life Effectiveness and Tolerability of Perampanel in Pediatric Patients Aged 4 Years or Older with Epilepsy: A Korean National Multicenter Study.

Background and PurposeThe US Food and Drug Administration approval for perampanel has only recently been expanded to patients as young as 4 years, and so there have been few real-life studies of the effects of perampanel in pediatric patients. The aim of this study was to determine the long-term efficacy, factors affecting treatment response, and tolerability of perampanel as an add-on therapy in pediatric patients aged 4 years or older with epilepsy.MethodsThis multicenter retrospective observational study collected data from pediatric epilepsy centers of four Korean national universities. Changes in the seizure frequency from baseline, adverse events, and retention rates were obtained at 3, 6, and 12 months. Adverse events and discontinuation profiles were obtained to assess tolerability.ResultsThis study included 220 children and adolescents (117 males and 103 females) aged 4 to 20 years. The overall response rate was 43.6%, and the seizure-freedom rate was 17.7%. Factors affecting a good treatment response were the absence of intellectual disability, small number of concomitant antiepileptic drugs, and low baseline seizure frequency. Eighty-eight patients (40%) experienced adverse events, but they mostly were of mild severity and resolved after the dose reduction or discontinuation of perampanel. The retention rates at 3, 6, and 12 months were 85.0%, 71.8%, and 50.5%, respectively.ConclusionsAdjunctive treatment with perampanel was efficacious and tolerated in pediatric patients aged 4 years or older with epilepsy. Early perampanel treatment may help to reduce the burden of their seizures and improve their quality of life.

E-Cadherin and Syndecan-1 Expression in Patients With Advanced Non-small Cell Lung Cancer Treated With Chemoradiotherapy.

The aim of the study was to investigate whether E-cadherin and syndecan-1 are molecular markers of advanced non-small cell lung cancer (NSCLC). The expression of E-cadherin and syndecan-1 (SDC1) was examined immunohistochemically on tissue specimens of 64 patients, with stage III disease at presentation. The obtained expression data were correlated with clinical parameters. Negative expression of SDC1 was correlated with squamous histology (p=0.002). E-cadherin positive expression was significantly associated with increased 2-year overall survival (OS) rate (p=0.032). In the multivariate Cox analysis, performance status 0-1 was an independent predictor of OS (p=0.001) and disease-free survival (DFS) (p=0.001). E-cadherin expression was an independent predictor of OS (p=0.007) and DFS (p=0.029). E-cadherin might be a prognostic factor for OS and DFS in advanced stage NSCLC patients. Further investigations are needed for the establishment of E-cadherin and syndecan-1 as molecular markers, affecting treatment response and survival.

Understanding the crosstalk of molecular factors and signaling pathways reveals novel biomarkers of cisplatin resistance in testicular germ cell tumors.

Testicular germ cell tumors (TGCTs) mostly affect young men, but fortunately belong to well curable solid tumors. Today, different treatment strategies are applied reaching excellent outcomes, and introduction of alternative approach of patient active surveillance or adjuvant chemotherapy after orchiectomy decreases number of unnecessary toxic treatments of young patients. Also for relapsing patients, salvage therapy offers high survival rates. However, small percentages of affected young men do not respond to conventional therapy regimen due to intrinsic or acquired therapy resistance. For closely watching of patients during active surveillance, patients' stratification due to their prognosis, detection of therapy resistance and early relapse before treatment initiation, reliable molecular biomarkers and diagnostic tools replacing conventional approaches are still needed. Complex understanding of disease development and progression as well as mechanisms of chemoresistance and their epigenetic or chronobiological regulation pre-requisite successful search for such novel biomarkers. In this review, we aimed to highlight the importance of crosstalk of different regulatory mechanisms and their key players affecting treatment response, and focus on their potential as novel molecular biomarkers and/or druggable targets.

Assessment of Anticholinergic Use After Fading of BTX-A Effects in Refractory Idiopathic Overactive Bladder: A Prospective Blinded Randomized Trial.

PurposeTo evaluate the efficacy and safety of re-treatment with anticholinergics on refractory idiopathic overactive bladder (OAB) previously treated with intravesical botulinum neurotoxin type A (BTX-A) injections.MethodsOne hundred patients were initially managed by intravesical injections of 100 IU of BTX-A. After the effects of BTX-A faded, patients were randomized into 2 groups: group A patients received solifenacin (10 mg) for 12 weeks (study group), while group B patients received placebo treatment for 12 weeks (control group), then subsequently received solifenacin (10 mg) for another 6 weeks. All patients underwent preoperative urodynamic testing. Patients were asked to complete the validated overactive bladder symptoms score (OABSS) and incontinence quality of life (I-QoL) instruments after the effects of intravesical BTX-A faded and at 12 weeks of follow-up. Univariate and multivariate analyses of the factors affecting treatment response were conducted.ResultsAt 12 weeks of follow-up, in group A, all OABSS items, including the total score, had improved significantly (P<0.0001). Group A had lower frequency and amplitude of detrusor overactivity and detrusor leak point pressure (P<0.0001, P=0.03, and P=0.01, respectively). Cystometric capacity also increased significantly (P=0.007), as did all I-QoL parameters. In a comparison of patients with failed treatment and patients with successful treatment, female sex, repeated intravesical BTX-A injections, and increased bladder capacity were statistically significant (P=0.001, P=0.0001, and P=0.002, respectively). Repeated intravesical BTX-A injections and increased bladder capacity were independent factors predicting treatment success.ConclusionsIn patients with refractory idiopathic OAB, reuse of anticholinergics could be an effective treatment option in patients after the effects of BTX-A fade. Repeated intravesical BTX-A injections and increased cystometric capacity could affect treatment response.

Abstract 2507: Genetic alterations affecting treatment response in locally advanced breast cancers

Abstract Resistance to chemotherapy remains a main cause of death among cancer patients. The primary aim of the present study was to identify genetic alterations predicting resistance to chemotherapy by whole exome sequencing (WES) of tumors subject to neoadjuvant sequential treatment with epirubicin and docetaxel. A long term goal is to identify biomarkers that may be applicable in testing for drug sensitivity prior to commencement of therapy for individual patients, leading to early administration of optimal treatment and sparing patients from side-effects of inefficient treatment. From a total of 100 patients treated with sequential monotherapy in the neoadjuvant setting, we performed WES on 146 tumor samples and matching blood samples from 51 patients. Biopsies for research were taken before treatment start, at the time of treatment switch and at the time of surgery. In the present work, we have analysed WES data to assess the mutational- and the copy number landscape and compared these results between patients having a good or poor response to the two administered drugs. SNV analysis revealed imbalance in several well established breast cancer related genes, between the different response groups. Copy number assessments revealed a general increase in copy number gains in chromosome 16 and increase of copy number losses in chromosomes 1 and X after treatment with epirubicin, indicating that subclones harbouring different types of CNVs are selected for during treatment. Correspondingly, after treatment with docetaxel we found a general increase of copy number gains in chromosome 8 and an increase of copy number losses in chromosomes 1 and 8. Finally, we assessed overall mutational signatures and observed shifts in these profiles during the two treatments. Citation Format: Andreas Venizelos, Stian Knappskog, Inger Marie Loees, Hans Petter Eikesdal, Per Eystein Lønning. Genetic alterations affecting treatment response in locally advanced breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2507.

Abstract 4528: Quantitative mass spectrometry to interrogate proteomic heterogeneity in metastatic lung adenocarcinoma and validate a novel somatic mutation CDK12-G879V

Abstract Lung cancer is the leading cause of cancer mortality. Tumor heterogeneity is a major cause of treatment failure. Intra- and inter-metastatic tumor heterogeneity has been demonstrated by next generation sequencing (NGS) studies. However, heterogeneity in the proteome and phosphoproteome has been less studied. Integrated proteogenomics is essential to understanding the intricacies of tumor heterogeneity affecting treatment response. Here, we performed integrated mass spectrometry-based proteogenomics to characterize spatial and temporal heterogeneity of an exceptional responder lung adenocarcinoma patient who survived with metastatic disease for more than 7 years while on combination treatment with HER2-targeted and chemotherapy. We employed Super-SILAC and TMT labeling strategies to quantify the proteome and phosphoproteome of a lung metastatic site and ten different metastatic progressive lymph nodes from our patient collected across a span of seven years, including at autopsy. To further interrogate the mass spectrometry data, patient-specific database was built to incorporate all the somatic variants identified by NGS. An extensive validation pipeline was built for confirmation of variant peptides. CRISPR-Cas9-mediated gene knockout, cell viability assays, and confocal microscopy were used for further validation of novel variants. A total of 6214 and 4061 proteins were identified from Super-SILAC and TMT experiments, respectively. 3648 proteins were identified and quantified in both experiments. More than 2000 proteins had catalytic activity, including kinases, phosphatases and metabolic enzymes. We identified 78 and 23 mutant peptides from Super-SILAC and TMT experiments, respectively. Three somatic variants, CDK12-G879V, FASN-R1439Q and HNRNPF-A105T, were confirmed using our variant peptide detection pipeline. Multiple reaction monitoring in a triple quadrupole mass spectrometer successfully identified and relatively quantified two of the variant tryptic peptides harboring the mutations, CDK12-G879V and FASN-R1439Q from the lung and lymph node metastatic sites, respectively. We investigated the consequences of loss of CDK12 function, as predicted from the novel CDK12-G879V mutant, in chemotherapy sensitivity. A549 lung adenocarcinoma cells, upon knockdown of CDK12, exhibited greater chemotherapy sensitivity that was rescued by wild type CDK12, but not by CDK12-G879V mutant. We demonstrate the importance of integrated proteogenomic analyses to identify variant peptides in mass spectrometry data and studying proteomic heterogeneity affecting treatment response. CDK12-G879V mutation results in a nonfunctional CDK12 kinase and chemotherapy susceptibility in lung metastatic sites, likely explaining the “cure” of lung metastatic sites in this patient. Citation Format: Xu Xhang, Khoa Dang P. Nguyen, Paul Rudnick, Nitin Roper, Emily Kawaler, Tapan K. Maity, Shivangi Awasthi, Shaojian Gao, Romi Biswas, Abhilash Venugopalan, Constance Cultraro, David Fenyo, Udayan Guha. Quantitative mass spectrometry to interrogate proteomic heterogeneity in metastatic lung adenocarcinoma and validate a novel somatic mutation CDK12-G879V [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4528.

Effect of ramelteon on insomnia severity: evaluation of patient characteristics affecting treatment response

We conducted a multicenter, open-label, observational study to evaluate the effectiveness and safety of ramelteon in patients with insomnia, and patient characteristics affecting treatment response in routine clinical practice. Eligible patients were aged ≥ 20 years, had a diagnosis of insomnia with difficulty falling asleep, and were scheduled to receive ramelteon 8 mg/day for 12 weeks. The primary objective was to evaluate the relationship between changes in insomnia severity [measured by the Insomnia Severity Index (ISI)] and patient characteristics. Changes in the physical (PCS-8) and mental (MCS-8) components of the Short Form-8 (SF-8), and safety were also investigated. 1527 patients received therapy; 40.5% were aged ≥ 65 years and 29.7, 56.9, and 13.4% had mild, moderate, or severe insomnia, respectively. At week 12, significant improvements in ISI score [mean change (standard deviation) from baseline, − 5.0 points (6.3); p < .0001], PCS-8 score [+ 2.40 points (8.71); p < .0001], and MCS-8 score [+ 3.68 points (9.47); p < .0001] were observed. Factors affecting ISI response or remission (based on adjusted odds ratios) included age ≥ 75 years, shorter disease duration, no alcohol intake, being employed full time, not taking concomitant medication for insomnia, and taking ramelteon more than 1 h before bedtime. In total, 5.9% of patients reported adverse drug reactions. In routine clinical practice, 12 weeks’ therapy with ramelteon was effective at improving insomnia severity, with no new safety concerns identified. Several patient characteristics were found to influence response to therapy.Clinical trial identifier: UMIN000013271

Going to extremes: determinants of extraordinary response and survival in patients with cancer.

Research into factors affecting treatment response or survival in patients with cancer frequently involves cohorts that span the most common range of clinical outcomes, as such patients are most readily available for study. However, attention has turned to highly unusual patients who have exceptionally favourable or atypically poor responses to treatment and/or overall survival, with the expectation that patients at the extremes may provide insights that could ultimately improve the outcome of individuals with more typical disease trajectories. While clinicians can often recount surprising patients whose clinical journey was very unusual, given known clinical characteristics and prognostic indicators, there is a lack of consensus among researchers on how best to define exceptional patients, and little has been proposed for the optimal design of studies to identify factors that dictate unusual outcome. In this Opinion article, we review different approaches to identifying exceptional patients with cancer and possible study designs to investigate extraordinary clinical outcomes. We discuss pitfalls with finding these rare patients, including challenges associated with accrual of patients across different treatment centres and time periods. We describe recent molecular and immunological factors that have been identified as contributing to unusual patient outcome and make recommendations for future studies on these intriguing patients.

Ten-year follow-up of children with hydatid cysts.

Aim:Hydatid cystic disease is an endemic parasitic disease that is common in the world. We aimed to review the demographic, clinical and laboratory findings, and treatments and outcomes of children with hydatid cyst disease, and to determine the factors affecting treatment response in two pediatric pulmonology centers in the central region of Turkey.Material and Methods:The clinical records of patients aged below 18 years who were followed up between January 2006 and December 2016 because of hydatid cyst disease were reviewed retrospectively. The patients’ ages at the time of diagnosis, sexes, living areas (rural /urban), dog contact history, presence of hydatid cyst in other family members, symptoms, organs involved, dimensions of cysts, laboratory results, treatments and post treatment responses, follow-up, and outcomes were noted.Results:In a period of 10 years, 50 pediatric patients were followed up with a diagnosis of hydatid cyst. The mean age was 9.3±0.5 years and 33 (66%) of the patients were male. Fifteen patients were living in a rural area and 35 were living in an urban area. Fifteen patients had a history of contact with a dog and 10% had a positive family history. Thirty-six patients had lung involvement, 25 had liver involvement, 14 (28%) had both lung and liver involvement, and six patients had organ involvement other than lung and liver. The indirect hemagglutination test for hydatid cyst was positive in 24 of 40 patients and Echinococcus granulosus-specific IgE positivity was detected in 8 of 17 patients. Surgery was performed in 31 patients with lung involvement and PAIR was performed in 13 patients who had liver involvement. Cyst excision was performed in two patients who had isolated spinal involvement. All patients were treated with albendazole, and additional praziquantel treatment was given to seven patients. Relapse occurred in seven patients in this period. The relapse frequency was higher in patients who had organ involvement other than in the lung and liver (p<0.05), and these patients’ treatment durations were longer compared with the others (p<0.05).Conclusion:Hydatid cysts can involve different organs in children. Patients with organ involvement other than the lung and liver should be followed up carefully in terms of recurrence.

One year effectiveness study of intravitreal aflibercept in neovascular age-related macular degeneration: a meta-analysis.

The current body of evidence on the efficacy and safety of aflibercept for age-related macular degeneration (AMD) is steadily growing as large clinical trials and observational studies are continually completed. Our aim was to analyse 1-year visual acuity (VA) outcomes in response to aflibercept therapy and identify factors affecting treatment response using evidence generated from a pooled analysis of current studies. A literature review of multiple electronic databases (EMBASE, MEDLINE, MedMEME) revealed 12 studies meeting inclusion and exclusion criteria for statistical analysis. Treatment posology, baseline patient characteristics, study type, sample size and 12-month change in VA were pooled in a meta-analysis with VA change as the main outcome. Data were then stratified by study design and posology in subgroup analyses. A meta-regression was conducted to regress 12-month VA change against posology, baseline VA and age. Users of aflibercept experienced an overall increase of 7.37 letters (95% confidence interval: 6.27-8.48, p heterogeneity: <0.001) in VA at 12months of follow-up. In subgroup analyses, mean VA change was higher for randomized control trials and cohorts following regular posology (>7 injections/year) compared to observational studies and irregular posology. The meta-regression showed larger VA gains with regular posology compared to an irregular posology, and decreased effect size as age increased. This meta-analysis strongly suggests improved VA outcomes at 12months in patients with wet AMD for 2.0mg aflibercept, comparable to but slightly lower than landmark trials. Increased injection frequency and younger age demonstrates a trend with improved outcomes.

Single vs multiple fraction palliative radiotherapy for uncomplicated painful bone metastases treated at University of Malaya Medical Centre: A single institutional Malaysian experience.

IntroductionThis study was conducted to compare pain response between single and multiple fraction palliative radiotherapy and to describe prognostic factors affecting treatment response in University of Malaya Medical Centre (UMMC).MethodsThe case records of 162 patients with uncomplicated painful bone metastases treated with palliative radiotherapy from 2006 to 2014 were analyzed. Treatment outcomes were pain score response, analgesic score response, response according to International Consensus Endpoints (complete response and overall response) at 4, 12, and 24 weeks, retreatment rate, symptomatic skeletal events (SSEs), and prognostic factors.ResultsAt 24 weeks, pain score response for single and multiple fraction group was 82.3% and 88.5%, analgesic score response was 54.8% and 61.5%, and overall response according to International Consensus Endpoint was 61.3% and 67.7%, respectively. There was no statistically significant difference in treatment response between the 2 treatment groups for all endpoints. ECOG (<2 vs ≥2: aOR 3.405, 95% CI 1.708‐6.790, P = .001) and primary breast and prostate (breast vs others: aOR 5.231, 95% CI 1.973‐13.869, P = .001; prostate vs others: aOR 5.522, 95% CI 1.493‐20.420, P = .01) were significant variables on multivariate analysis.ConclusionSingle fraction radiotherapy is as effective as multiple fraction radiotherapy for the palliation of uncomplicated bone metastases.