Long-term Benefits For Patients Research Articles

Uptake and survival effects of minimally invasive surgery for lung cancer: A population-based study

IntroductionDespite growing evidence supporting the safety of minimally invasive surgery (MIS) in the treatment of lung cancer, its uptake is still variable and its outcomes debated. This study examines the factors associated with MIS uptake and its effects on survival in patients with non-small cell lung cancer (NSCLC). MethodsAll patients in the Canadian province of Ontario with early stage NSCLC (stage I/II) from 2007 to 2017 were included. A logistic regression identified the predictors of MIS uptake, and a flexible parametric model was used to estimate survival rates based on MIS versus open resection. ResultsIn total, 8,988 patients underwent surgical resection; 53.6% had MIS. Year of diagnosis was associated with MIS uptake (OR = 1.33, p < 0.001); patients in later years were more likely to receive MIS. Rurality was a significant predictor of MIS, though distance from nearest regional cancer center did not predict MIS utilization. Patients with stage II disease were less likely to receive MIS compared to those with stage I disease (OR = 0.44, p < 0.001). MIS had a significantly higher 5-year survival compared to open resection for stage I and II disease. Patients >70 years had the greatest 5-year survival benefit from MIS. ConclusionsWe observed a substantial long-term survival benefit in patients undergoing MIS for early stage NSCLC. This difference was most pronounced in the oldest age group. These findings support the use of MIS in the treatment of lung cancer and challenge the notion that MIS compromises oncologic outcomes.

Acupuncture and its Effects on Chronic Pain

Acupuncture is an complementary form of medicine that has relatively recently become a component of traditional Chinese medicine (TCM). It involves the application of thin needles at specific points throughout the body, although initially, general areas instead of points were used. There are estimated to be about 395 different points that can be utilized, and the technique behind using these points can vary widely between practitioners. In addition to acupuncture points, TCM is said to use meridians or pathways along with qi, or energy flows. In terms of acupunctures’ utility, it has been known to treat a variety of ailments ranging from pain and headaches to sleep disturbances, but it's true benefits continue to be questioned. To date, thousands of studies have been performed in regards to its efficacy with varying conclusions. Once considered to be “pseudomedicine”, this ancient technique has been found to provide long-term benefits for patients with chronic pain. This manuscript aims at providing a brief history of acupuncture and examines studies in favor of its relief of chronic pain.

Bariatric surgery proves long-term benefit in patients with cirrhosis.

BackgroundObesity is commonly observed in patients with cirrhosis, especially with the increasing prevalence of non-alcoholic steatohepatitis (NASH). Bariatric surgery has been avoided in these patients given concerns about increased perioperative risk; therefore, data are lacking regarding long-term outcomes. In this study, we aimed to evaluate the long-term outcomes of patients with cirrhosis who underwent bariatric surgery.MethodsWe reviewed the charts of adult patients with compensated cirrhosis who underwent bariatric surgery after they were prospectively enrolled between February 23, 2009 and November 9, 2011, and followed in a pilot study for evaluation of bariatric surgery outcomes. Only patients with more than 4 years of follow-up were included in the analysis. Data regarding their liver disease, metabolic status, and survival were collected. A descriptive analysis was performed.ResultsThe cohort consisted of 10 patients, of whom 7 were females. The median post-surgical follow-up was 8.7 years (± 1.4 years). All patients had biopsy-proven NASH; two patients had concurrent, untreated hepatitis C infection. During the observation period, there was a mean weight loss of 24 kg (19.2% of total body weight pre surgery, P < 0.001) and only one patient regained weight to the baseline pre-surgical measurement. One patient who was not eligible for transplant developed hepatic encephalopathy 3 years after surgery and later died. The remainder of the patients did not have any hepatic decompensation, cardiovascular event, or mortality. Except for one patient with Gilbert syndrome, bilirubin was normal in all patients at last follow-up.ConclusionsBariatric surgery in patients with compensated cirrhosis can lead to sustained weight loss and stable hepatic function on long-term follow-up.

Tyrosine metabolism in health and disease: slow-release amino acids therapy improves tyrosine homeostasis in phenylketonuria.

Phenylalanine (Phe) hydroxylase (PAH) deficiency leads to hyperphenylalaninemia (HPA) and tyrosine (Tyr) depletion. We investigated Tyr homeostasis in patients with PAH deficiency and the effect of a slow-release amino acids therapy in phenylketonuria (PKU). We performed four complementary investigations: (1) Tyr concentrations were monitored in 114 patients (10.6±11.9years) with PKU on dietary treatment supplemented with traditional amino acid formulations (n=52, 1175 samples) or non-PKU HPA on a free diet (n=62, 430 samples); (2) Tyr metabolism in PKU was quantitatively evaluated in three patients by a simple Tyr oral loading test (100mg/kg); (3) diurnal and (4) long-term Tyr concentrations were evaluated in 5 and 13 patients with PKU, respectively, who switched from traditional to slow-release amino acids therapy. 1) Tyr concentrations in the PKU population were subnormal and significantly lower than in non-PKU HPA (p<0.01); (2) the response to a Tyr loading test in PKU was normal, with basal Tyr concentrations reached within 12h; (3) the diurnal metabolic profile in patients on slow-release amino acids therapy revealed higher morning fasting and nocturnal Tyr concentrations with respect to traditional therapy (p<0.01); (4) this picture was confirmed at follow-up, with normalization of morning fasting Tyr concentrations in patients on slow-release amino acids therapy (p<0.01) and unchanged Phe control (p=0.19). Slow-release amino acids therapy can improve Tyr homeostasis in PKU. If associated to optimized Phe control, such a metabolic goal may allow long-term clinical benefits in patients with PKU.

Long-term prognostic benefit of beta-blockers use after discharge in patients with Tako-Tsubo syndrome

Abstract Background Tako-tsubo Syndrome (TS) seems to be associated with a catecholamine-mediated mechanism. However, the impact of beta-blockers (BB) in-hospital and after discharge still remain uncertain. Objectives: The purpose of the study was to examine whether BB use after discharge in patients with TS, was associated with lower long-term mortality and recurrence. Methods Using a national multicentre large-scale inpatient database (RETAKO Registry), we analysed patients with a definitive TS diagnosis. Results A total of 970 patients were analysed (568 with BB therapy and 402 no-BB therapy). After discharge and over a median of follow-up of 1.1 years, treatment with BB have no shown prognostic effectiveness in terms of mortality and TS recurrence in unadjusted and adjusted Cox analysis (HR 0.86; 95% CI: 0.59 to 1.27; and 0.95; 95% CI: 0.57–1.13, respectively). Conclusions This data suggests that use of beta-blockers after hospital discharge has not shown long-term prognostic benefit in patients with Tako-tsubo Syndrome. Prognostic impact of BB in TS. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Retako webpage was funded by a non-conditioned Astrazeneca scholarship.

Adjuvant Electronic Brachytherapy For Patients With Endometrial Cancer

Brachytherapy plays a fundamental role in the adjuvant treatment of endometrial cancer (EC) to decrease vaginal cuff recurrence. Traditionally high dose rate (HDR) brachytherapy with Iridium 192 (Ir-192) had been used, but the recent development of electronic brachytherapy (eBT) based on X-ray emissions could be an alternative. Our objectives are to analyze the local recurrence in EC treated with eBT, toxicity profile and to compare with series from the literature with HDR Ir-192 brachytherapy. From September 2015 to January 2019, 271 patients with endometrial cancer were treated with vaginal eBT at our institution. 117 patients received vaginal eBT as monotherapy and 154 as a boost after external beam radiation therapy (EBRT). We used different dose-fractionation schedules: total dose was 15 Gy in 3 fractions or 14 Gy in 2 for eBT as a boost to EBRT; and 25 Gy in 5 fractions or 21 Gy in 3 fractions for exclusive eBT. Acute and late toxicities were recorded using Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Data was collected retrospectively. The median follow-up was 24 months. The average age was 66 years. 70% were diagnosed as endometrioid carcinoma (Type I). According to the International Federation of Gynaecology and Obstetrics (FIGO) classification: 30% FIGO IA; 39% FIGO IB and 31% FIGO ≥IIA. Acute toxicity: 33% had vaginal toxicity; 10% had urinary toxicity; 8% had rectal toxicity and all of them were ≤Grade 1 (G1) or G2. G1-G2 chronic toxicity was observed: 10% vaginal toxicity; 1% urinary toxicity; 8% rectal toxicity; 3 patients (1.5%) had G3 rectal late toxicity. A statistically significant difference was found in the rectal toxicity observed at the patients treated with EBRT plus eBT versus eBT as monotherapy (p = 0.008). 8 patients had locoregional recurrence, 8 had systemic recurrence and 12 had both recurrences. Only 1 vaginal cuff relapse was observed. Our series, shows an increase in acute G1 vaginal mucosa toxicity with respect to HDR Ir-192 brachytherapy (33% vs 15.8%), but reduction of late vaginal mucosal toxicity (10% eBT vs. 23% Ir-192). Vaginal cuff recurrence results were better than the literature (0.36% eBT vs. 0.7-1.4% Ir-192). eBT at endometrial cancer is a feasible alternative to HDR brachytherapy with Ir-192 in effectiveness with an acceptable grade 1 acute toxicity. It has given long-term benefits for patients, providing the same dosimetric coverage in the area of treatment as HDR brachytherapy with reduction in the dose of organs at risk, benefits for staff and health system as mobility, versatility and ease of installation of the equipment. Further research is needed to establish eBT as an alternative to high dose rate brachytherapy.

DESTINATION: a phase 3, multicentre, randomized, double-blind, placebo-controlled, parallel-group trial to evaluate the long-term safety and tolerability of tezepelumab in adults and adolescents with severe, uncontrolled asthma

BackgroundTezepelumab is a human monoclonal antibody that blocks the activity of the epithelial cytokine thymic stromal lymphopoietin. The efficacy, safety and oral corticosteroid-sparing potential of tezepelumab are being investigated in two ongoing, phase 3, randomized, double-blind, placebo-controlled studies (NAVIGATOR [NCT03347279] and SOURCE [NCT03406078]). DESTINATION (NCT03706079) is a long-term extension (LTE) of these studies.MethodsDESTINATION is a randomized, double-blind, placebo-controlled LTE study in adults (18–80 years old) and adolescents (12–17 years old) with severe, uncontrolled asthma who are receiving treatment with medium- or high-dose inhaled corticosteroids plus at least one additional controller medication with or without oral corticosteroids. The study population will comprise patients who complete the 52- and 48-week NAVIGATOR and SOURCE studies, respectively. Patients who were randomized to receive tezepelumab 210 mg every 4 weeks (Q4W) in either predecessor study will continue to receive this regimen for 1 year; those who were previously randomized to receive placebo will be re-randomized (1:1) to receive either tezepelumab 210 mg Q4W or placebo for 1 year. Patients will receive their prescribed controller medications throughout DESTINATION and study physicians will have the opportunity to down- or up-titrate dosage of these medications, if appropriate. The primary objective is to evaluate the long-term safety and tolerability of tezepelumab over 104 weeks (inclusive of the treatment period of either predecessor study). The secondary objective is to assess the long-term effect of tezepelumab on asthma exacerbations. Patients recruited from SOURCE will be followed up post-treatment for 12 weeks. Patients recruited from NAVIGATOR who complete 100 weeks of tezepelumab treatment will be eligible for either 12 weeks of follow-up or a 36-week extended follow-up during which the clinical benefit of tezepelumab after treatment cessation will be investigated.DiscussionDESTINATION will evaluate the long-term safety, tolerability and efficacy of tezepelumab versus placebo with continued dosing for up to 2 years. DESTINATION will also evaluate the clinical effect of tezepelumab after treatment cessation. This LTE study aims to elucidate the long-term safety implications of receiving tezepelumab and to assess its potential long-term treatment benefits in patients with severe, uncontrolled asthma.Trial registrationNCT03706079 (ClinicalTrials.gov). Registered 15 October 2018.

Cardiac Rehabilitation Is Associated With Improved Long-Term Outcomes After Coronary Artery Bypass Grafting

BackgroundAlthough cardiac rehabilitation (CR) has proven to have short- and mid-term benefit in treatment of coronary artery disease, its long-term benefit in patients who have undergone coronary artery bypass grafting (CABG) is less certain. Our objective was to examine the late outcomes of patients who attended CR within the first year after CABG. MethodsAdult CABG patients referred to Toronto Rehabilitation Institute (CR group: were referred and attended at least 1 session; No-CR group: were referred but did not attend) between January 1996 and September 2008 were identified through linkages with clinical and provincial administrative databases for comorbidities and outcome ascertainment. The primary outcome was a composite of all-cause mortality, acute myocardial infarction, stroke or repeat revascularization (major adverse cardiac and cerebrovascular events [MACCE]). The secondary outcome was all-cause mortality. Multivariable Cox proportional hazard models were used to assess the CR treatment effect, adjusting for baseline characteristics. ResultsThe study cohort consisted of 5,000 patients—3,685 (73.7%) in the CR group and 1,315 (26.3%) in the No-CR group. Median referral time was 32.5 days, and follow-up was 13.1 years. The CR group patients, compared with the No-CR group, were younger (age 62.6 ± 9.6 vs 64.0 ± 10.5 years), were more likely to be male (85.0% vs 79.5%), and had fewer cardiac comorbidities. In adjusted analyses, the CR group was associated with decreased MACCE (hazard ratio 0.83, 95% confidence interval 0.75-0.91, P < 0.0001) and a higher adjusted survival at 15 years (66.3% vs 60.1%, hazard ratio 0.76, 95% confidence interval 0.68-0.84, P < 0.0001), as compared with the No-CR group. ConclusionsThere was a reduction in MACCE and late mortality associated with CR attendance, highlighting the importance of patient referral and participation in CR after CABG.

Non-intubated thoracoscopic lobectomies for lung cancer: an exploratory systematic review and meta-analysis.

Our goal was to assess the safety, feasibility and oncological outcomes of non-intubated thoracoscopic lobectomies for non-small-cell lung cancer (NSCLC). A comprehensive search was performed in EMBASE (via Ovid), MEDLINE (via PubMed) and Cochrane CENTRAL from January 2004 to March 2020. Studies comparing non-intubated anaesthesia with intubated anaesthesia for thoracoscopic lobectomy for NSCLC were included. An exploratory systematic review and a meta-analysis were performed by combining the reported outcomes of the individual studies using a random effects model. For dichotomous outcomes, risk ratios were calculated and for continuous outcomes, the mean difference was used. Three retrospective cohort studies were included, with a total of 204 patients. The comparison between non-intubated and intubated patients undergoing thoracoscopic lobectomy showed no statistically significant differences in postoperative complication rates [risk ratio 0.65, 95% confidence interval (CI) 0.36-1.16; P = 0.30; I2 = 17%], operating times (mean difference -12.40, 95% CI -28.57 to 3.77; P = 0.15; I2 = 48%), length of hospital stay (mean difference -1.13, 95% CI -2.32 to 0.05; P = 0.90; I2 = 0%) and number of dissected lymph nodes (risk ratio 0.92, 95% CI 0.78-1.25; P = 0.46; I2 = 0%). Despite the limitation of only 3 papers included, awake and intubated thoracoscopic lobectomies for resectable NSCLC seem to have comparable perioperative and postoperative outcomes. Nevertheless, the oncological implications of the non-intubated approach should be considered. The long-term benefits for patients with lung cancer need to be carefully assessed.

Reinvigorating exhausted CD8+ cytotoxic T lymphocytes in the tumor microenvironment and current strategies in cancer immunotherapy.

Immunotherapy has revolutionized the treatment of cancer in recent years and achieved overall success and long-term clinical benefit in patients with a wide variety of cancer types. However, there is still a large proportion of patients exhibiting limited or no responses to immunotherapeutic strategy, some of which were even observed with hyperprogressive disease. One major obstacle restricting the efficacy is that tumor-reactive CD8+ T cells, which are central for tumor control, undergo exhaustion, and lose their ability to eliminate cancer cells after infiltrating into the strongly immunosuppressive tumor microenvironment. Thus, as a potential therapeutic rationale in the development of cancer immunotherapy, targeting or reinvigorating exhausted CD8+ T cells has been attracting much interest. Hitherto, both intrinsic and extrinsic mechanisms that govern CD8+ T-cell exhaustion have been explored. Specifically, the transcriptional and epigenetic landscapes have been depicted utilizing single-cell RNA sequencing or mass cytometry (CyTOF). In addition, cellular metabolism dictating the tumor-infiltrating CD8+ T-cell fate is currently under investigation. A series of clinical trials are being carried out to further establish the current strategies targeting CD8+ T-cell exhaustion. Taken together, despite the proven benefit of immunotherapy in cancer patients, additional efforts are still needed to fully circumvent limitations of exhausted T cells in the treatment. In this review, we will focus on the current cellular and molecular understanding of metabolic changes, epigenetic remodeling, and transcriptional regulation in CD8+ T-cell exhaustion and describe hypothetical treatment approaches based on immunotherapy aiming at reinvigorating exhausted CD8+ T cells.

Rhetorical work and medical authority: Constructing convincing cases in insurance medicine.

This article explores general practitioners' (GPs) persuasive efforts in cases where biomedical evidence is absent but expected. Health insurance in Western countries is based on the biomedical ideal that legitimate complaints should have objective causes detectable by medical examination. For GPs responsible for assessing sickness and incapacity for work, the demand for objective evidence can be problematic: what if they as experts deem that a patient is in fact sick and eligible for benefits, but are unable to provide objective evidence to that fact? How can they convince bureaucrats in the insurance system to accept their judgment? Taking 'medically unexplained symptoms' as my case, I draw on focus group and follow-up interviews with GPs in Norway to explore how GPs attempt to persuade bureaucrats to accept their professional judgment. Proposing the concept of 'rhetorical work', I reconstruct a typology of such work that doctors engage in to influence bureaucratic decision-making and provide long-term health benefits for patients. I then discuss the potential societal implications of GPs' rhetorical practices and the applications of the concept of rhetorical work in future research.

“I Dreamed of My Hands and Arms Moving Again”: A Case Series Investigating the Effect of Immersive Virtual Reality on Phantom Limb Pain Alleviation

Phantom limb pain (PLP) is a type of chronic pain that follows limb amputation, brachial plexus avulsion injury, or spinal cord injury. Treating PLP is a well-known challenge. Currently, virtual reality (VR) interventions are attracting increasing attention because they show promising analgesic effects. However, most previous studies of VR interventions were conducted with a limited number of patients in a single trial. Few studies explored questions such as how multiple VR sessions might affect pain over time, or if a patient's ability to move their phantom limb may affect their PLP. Here we recruited five PLP patients to practice two motor tasks for multiple VR sessions over 6 weeks. In VR, patients “inhabit” a virtual body or avatar, and the movements of their intact limbs are mirrored in the avatar, providing them with the illusion that their limbs respond as if they were both intact and functional. We found that repetitive exposure to our VR intervention led to reduced pain and improvements in anxiety, depression, and a sense of embodiment of the virtual body. Importantly, we also found that their ability to move their phantom limbs improved as quantified by shortened motor imagery time with the impaired limb. Although the limited sample size prevents us from performing a correlational analysis, our findings suggest that providing PLP patients with sensorimotor experience for the impaired limb in VR appears to offer long-term benefits for patients and that these benefits may be related to changes in their control of the phantom limbs' movement.

Abstract 4493: Enhancer reprogramming contributes to anti-PD1 resistance in melanoma

Abstract Immune checkpoint blockade therapy has improved clinical responses and long-term survival benefit for patients with advanced melanoma, however the response rate is modest and a large fraction of treated patients do not experience clinical benefits. Therefore, there is tremendous need to identify combination strategies to improve responses and to overcome resistance to therapy. Emerging data suggest that epigenetic drugs can improve the responses to immunotherapy. However, we have limited understanding of epigenetic mechanisms that characterize responses to Immune checkpoint blockade therapy. Therefore, we generated comprehensive epigenomic landscapes of 36 samples from anti PD-1 treated metastatic melanoma patients by profiling 6 histone markers. To determine correlation of epigenetic features with gene expression, we generated RNA-Access data for 12 matched samples. We determined chromatin states using ChromHMM and ChromHMM profiling consolidated using Epilogos. Analysis of chromatin state differences and associated individual mark profiles with response rate suggested that pre-treatment samples from anti PD-1 non-responsive patients contain higher active enhancer state (enriched for H3K27Ac) compared to responsive patients. Many of these enhancers targeted key regulators of pathways that are shown to mediate resistance to immune checkpoint blockade therapy. Importantly, aberrant expression of these genes correlated well with enhancer gains. Inhibition of enhancers with bromodomain inhibitor along with anti PD-1 significantly decreased the tumor volume by increased T cell infiltration. Together, these findings reveal that enhancer gains on key oncogenes associate with poor response to Immune checkpoint therapy which could be potentially used for stratifying responder and resistant lesions. Citation Format: Mayinuer Maitituoheti, Ming Tang, Christopher J. Terranova, Emily Keung, Katarzyna J. Tomczak, Jennifer Wargo, Kunal Rai. Enhancer reprogramming contributes to anti-PD1 resistance in melanoma [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 4493.

Cardiac resynchronization therapy in New York Heart Association class-IV patients dependent on intravenous drugs or invasive supportive treatments.

AimsWe sought to evaluate the effectiveness of cardiac resynchronization therapy (CRT) in far‐advanced heart failure (FA‐HF) patients with New York Heart Association (NYHA) class‐IV status and dependency on intravenous drugs (IVDs) and/or invasive supportive treatments (ISTs).Methods and resultsAmong 305 patients who underwent CRT implantation between October 2005 to December 2019, we identified 17 FA‐HF patients with NYHA class‐IV status and dependency on IVDs (inotropes, diuretics, vasopressors, or vasodilators) and/or ISTs (extracorporeal membranous oxygenator or continuous renal replacement therapy). All patients (median age = 68.7 years, non‐ischaemic cardiomyopathy = 15) remained dependent on several IVDs (2.2 ± 1.3 per patient) and/or ISTs for 11.3 ± 7.8 days due to multiple tapering failure (4.3 ± 3.2 per patient) before CRT implantation. However, 14 (82%) patients were successfully weaned from IVDs/ISTs within 5.2 ± 5.3 days following CRT, and 12 (71%) stayed alive for more than 1 year free of ventricular assist device or heart transplantation with symptom improvement (≥1 NYHA class) and a reduced annual HF hospitalization rate (P = 0.002). Considerable improvements in ventricular systolic function (P = 0.004) and volumetric reverse remodelling (P = 0.007) were noticed during the long‐term follow‐up period (35 ± 15 months post‐CRT). The ventricular assist device/heart transplantation/death‐free survival rate post‐CRT was 71% and 65% at 1 and 3 years, respectively.ConclusionsCardiac resynchronization therapy implantation may be a feasible treatment that can offer short‐term and long‐term clinical benefits for NYHA class‐IV FA‐HF patients who are dependent on IVDs/ISTs. When considering treatment options, CRT should not be prematurely excluded solely based on a patient's dependency on IVDs/ISTs without first attempting to identify favourable CRT response factors.

Thoracoscopic Sympathectomy for Palmar and Axillary Hyperhidrosis

This video is a step-by-step description of thoracoscopic sympathectomy. Sweating is essential for thermoregulation. Hyperhidrosis is a condition of excess sweating from the eccrine glands and is associated with severe suffering for patients of all ages. It often worsens during adolescence. A generalised and focal type of hyperhidrosis which affects mainly the face, armpits, hands and feet can be distinguished from the focal variant. Thoracic sympathectomy has become the standard treatment for palmar and axillary hyperhidrosis worldwide. The procedure is performed in the supine position with the upper body elevated about 30° in an adolescent patient. Both arms are abducted at 90° and single tube endotracheal ventilation is employed. A 3 mm trocar is placed in the anterior axillary line for a 3 mm 30° optic. A 5 mm trocar placed on the anterior axillary line (or breast fold in female patients) of the 4th or 5th intercostal space is used for the bipolar forceps. The sympathetic trunk and ganglia T 2 - 4 are identified and coagulated over the heads of ribs. The thoracoscopic approach to focal palmar and axillary hyperhidrosis allows clear identification of the sympathetic structures on each side. Under direct vision, selective ablation of the ganglia and sympathetic trunk provides long-term benefit for patients.

Chemical strategies to overcome resistance against targeted anticancer therapeutics.

Emergence of resistance is a major factor limiting the efficacy of molecularly targeted anticancer drugs. Understanding the specific mutations, or other genetic or cellular changes, that confer drug resistance can help in the development of therapeutic strategies with improved efficacies. Here, we outline recent progress in understanding chemotype-specific mechanisms of resistance and present chemical strategies, such as designing drugs with distinct binding modes or using proteolysis targeting chimeras, to overcome resistance. We also discuss how targeting multiple binding sites with bifunctional inhibitors or identifying collateral sensitivity profiles can be exploited to limit the emergence of resistance. Finally, we highlight how incorporating analyses of resistance early in drug development can help with the design and evaluation of therapeutics that can have long-term benefits for patients.

Early M-Protein Dynamics Predicts Progression-Free Survival in Patients With Relapsed/Refractory Multiple Myeloma.

This study aimed to predict long‐term progression‐free survival (PFS) using early M‐protein dynamic measurements in patients with relapsed/refractory multiple myeloma (MM). The PFS was modeled based on dynamic M‐protein data from two phase III studies, POLLUX and CASTOR, which included 569 and 498 patients with relapsed/refractory MM, respectively. Both studies compared active controls (lenalidomide and dexamethasone, and bortezomib and dexamethasone, respectively) alone vs. in combination with daratumumab. Three M‐protein dynamic features from the longitudinal M‐protein data were evaluated up to different time cutoffs (1, 2, 3, and 6 months). The abilities of early M‐protein dynamic measurements to predict the PFS were evaluated using Cox proportional hazards survival models. Both univariate and multivariable analyses suggest that maximum reduction of M‐protein (i.e., depth of response) was the most predictive of PFS. Despite the statistical significance, the baseline covariates provided very limited predictive value regarding the treatment effect of daratumumab. However, M‐protein dynamic features obtained within the first 2 months reasonably predicted PFS and the associated treatment effect of daratumumab. Specifically, the areas under the time‐varying receiver operating characteristic curves for the model with the first 2 months of M‐protein dynamic data were ~ 0.8 and 0.85 for POLLUX and CASTOR, respectively. Early M‐protein data within the first 2 months can provide a prospective and reasonable prediction of future long‐term clinical benefit for patients with MM.

Percutaneous mitral valve repair with MitraClip XTR for acute mitral regurgitation due to papillary muscle rupture

Papillary muscle rupture is an infrequent and highly morbid mechanical complication of acute myocardial infarction. Surgical repair or replacement is traditionally considered first-line therapy. However, many of these patients present in extremis with prohibitively high surgical risk. Repair of mitral regurgitation with the MitraClip device (Abbot Vascular, Menlo Park, CA, USA) is an established therapy to treat degenerative and functional mitral regurgitation. We present a case of successful repair of severe mitral regurgitation due to papillary muscle rupture in the setting of acute myocardial infarction. A two-clip strategy resulted in mild residual mitral regurgitation with resolution of cardiogenic shock and refractory hypoxemia requiring veno-venous extracorporeal membrane oxygenation. Six-month follow-up echocardiogram identified durable results with mild mitral regurgitation and left ventricular ejection fraction of 63 %. Our case demonstrates that percutaneous mitral valve repair with MitraClip is a well-tolerated procedure that can provide acute and long-term benefit for patients with acute mitral regurgitation due to papillary muscle rupture who are at prohibitively high surgical risk.<Learning Objective: Our case illustrates the role of MitraClip in acute mitral regurgitation due to papillary muscle rupture in cardiogenic shock as an alternative to surgical intervention in extremely high-risk patients.>

A Longitudinal Study Of Combined Exercise Intervention With Internet And Social Media For Breast Cancer Patient

PURPOSE: Breast cancer patients in treatment suffer from long-term side effects that seriously influence their physical and mental health. The aim of this study was to examine differences in health-related outcomes between a 12-week remotely-guided combined exercise (CE) intervention group and a usual care (UC) group after one year for breast cancer patients. METHODS: In phases I~III, 60 patients (51.2 ± 7.9 years) with breast cancer (BC) who completed chemotherapy/ postoperative radiotherapy within the previous 4 months to 2 years participated in a randomized controlled trial intervention of combined exercise with remote guidance. Eligible participants were approached to assess cancer-related quality of life (QOL), muscle strength, cardiorespiratory endurance and physical activity (PA) barriers after one year. RESULTS: The result demonstrated that after one year the CE group reported higher in vitality-related QOL (5.776, CI 0.987, 10.565, ES=0.360), mental health-related QOL (9.938, CI 4.146, 15.729, ES=0.512), leg strength and endurance (2.880, CI 1.337, 4.423, ES=0.557), strength and endurance of upper extremities (2.745, CI 1.076, 4.415, ES=0.491), and lower physical activity (PA) hindrance (5.120, CI 1.976, 8.264, ES=0.486) than the UC group. CONCLUSIONS: The CE group had significant differences from the UC group in quality of life, muscle strength, cardiopulmonary endurance and physical activity participation. These findings showed that the combined exercise intervention with remote guidance produce a long-term benefits for breast cancer patients.

Effect of Modified LMB 89± Rituximab Regimen on Long-Term Benefits for Patients's with Burkitt Lymphoma

To investigate the effect of modified LMB 89± rituximab regimen on long-term clinical benefit for patients with Burkitt lymphoma. Clinical data of 43 patients with Burkitt lymphoma were collected and retrospectively analyzed in the period from July 2006 to October 2017. Forty-three patients were divided into 2 groups, including Hyper-CVAD regimen, R-EPOCD regimen or VDCLP regimen treated group as control (20 patients) and modified regimen group with modified LMB 89±rituximab regimen (23 patients); the event-free survival (EFS) rate, overall survival (OS) rate, cumulative incidence of relapse (CIR), non-relapse mortality rate (NRM) and adverse reaction incidence of 2 groups were compared. At the same time, the efficacy analysis for patients of modified regimen group was performed according to age and using rituximab or no. The EFS rate and OS rate of modified regimen group were significantly higher than those of control group (P＜0.05). The CRR rate and NRM rate of modified regimen group were significantly lower than those of control group (P＜0.05). The EFS rate and OS rate of patients for ＜40 years old were significantly higher than those of patients for ≥40 years old in modified regimen group (P＜0.05). The EFS rate and OS rate of patients with rituximab were significantly higher than those of patients without rituximab in modified regimen group (P＜0.05). There was no significant difference in the adverse reaction incidence between 2 groups (P＞0.05). Modified LMB 89± rituximab regimen in the treatment of patients with Burkitt lymphoma can efficiently prolong survival time and shows the better safety; and the remigen combined with rituximab is more helpful to improve the clinical prognosis and show the better clinical effects for the patients≤40 years old.