IMpassion132 double-blind randomised phase III trial of chemotherapy with or without atezolizumab for early relapsing unresectable locally advanced or metastatic triple-negative breast cancer.

BACKGROUND: Immune checkpoint inhibitors improve the efficacy of first-line chemotherapy for patients with programmed death-ligand 1 (PD-L1)-positive unresectable locally advanced/metastatic triple-negative breast cancer (aTNBC), but randomised data in rapidly relapsing aTNBC are scarce. PATIENTS AND METHODS: IMpassion132 (NCT03371017) enrolled patients with aTNBC relapsing <12 months after last chemotherapy dose (anthracycline and taxane required) or surgery for early TNBC. PD-L1 status was centrally assessed using SP142 before randomisation. Initially patients were enrolled irrespective of PD-L1 status. From August 2019, enrolment was restricted to PD-L1-positive (tumour immune cell ≥1%) aTNBC. Patients were randomised 1:1 to placebo or atezolizumab 1200 mg every 21 days with investigator-selected chemotherapy until disease progression or unacceptable toxicity. Stratification factors were chemotherapy regimen (carboplatin plus gemcitabine or capecitabine monotherapy), visceral (lung and/or liver) metastases and (initially) PD-L1 status. The primary endpoint was overall survival (OS), tested hierarchically in patients with PD-L1-positive tumours and then, if positive, in the modified intent-to-treat (mITT) population (all-comer patients randomised pre-August 2019). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR) and safety. RESULTS: Among 354 patients with rapidly relapsing PD-L1-positive aTNBC, 68% had a disease-free interval of <6 months and 73% received carboplatin/gemcitabine. The OS hazard ratio was 0.93 (95% confidence interval 0.73-1.20, P = 0.59; median 11.2 months with placebo versus 12.1 months with atezolizumab). mITT and subgroup results were consistent. Median PFS was 4 months across treatment arms and populations. ORRs were 28% with placebo versus 40% with atezolizumab. Adverse events (predominantly haematological) were similar between arms and as expected with atezolizumab plus carboplatin/gemcitabine or capecitabine following recent chemotherapy exposure. CONCLUSIONS: OS, which is dismal in patients with TNBC relapsing within <12 months, was not improved by adding atezolizumab to chemotherapy. A biology-based definition of intrinsic resistance to immunotherapy in aTNBC is urgently needed to develop novel therapies for these patients in next-generation clinical trials.

Optimal adjuvant therapy in older (≥70 years of age) women with low-risk early-stage breast cancer.

Older women are under-represented in breast cancer (BC) clinical trials, and treatment guidelines are primarily based on BC studies in younger women. Studies uniformly report an increased incidence of local relapse with omission of breast radiation therapy. Review of the available literature suggests very low rates of distant relapse in women ≥70 years of age. The incremental benefit of endocrine therapy in decreasing rate of distant relapse and improving disease-free survival in older patients with low-risk BC remains unclear. Integration of molecular genomic assays in diagnosis and treatment of estrogen receptor positive BC presents an opportunity for optimizing risk-tailored adjuvant therapies in ways that may permit treatment de-escalation among older women with early-stage BC. The prevailing knowledge gap and lack of risk-specific adjuvant therapy guidelines suggests a compelling need for prospective trials to inform selection of optimal adjuvant therapy, including omission of adjuvant endocrine therapy in older women with low risk BC.

Patient-reported outcomes predict survival and adverse events following anticancer treatment initiation in advanced HER2-positive breast cancer.

BACKGROUND: The prognostic value of patient-reported outcomes (PROs) has been minimally explored in advanced breast cancer (BC), and their comparative prognostic performance against Eastern Cooperative Oncology Group performance status (ECOG PS) is largely unknown. PATIENTS AND METHODS: This study pooled individual participant data from clinical trials CLEOPATRA, EMILIA, and MARIANNE. Pre-treatment PRO associations with overall survival (OS), progression-free survival (PFS), and grade ≥3 adverse events were evaluated via Cox proportional hazards regression. Prognostic performance was assessed with the C-statistic (c). PRO values were collected via the Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire. All analyses were stratified by study and treatment arms. Analyses adjusted for known prognostic variables were conducted. Exploratory analysis of the prognostic performance of PROs compared to ECOG PS was undertaken. RESULTS: The study included data from 2894 patients initiated on contemporary therapies including pertuzumab (n = 765), trastuzumab (n = 1173), trastuzumab emtansine (n = 1225), taxanes (n = 1173), lapatinib (n = 496), and capecitabine (n = 496). On univariable and adjusted analysis, patient-reported physical well-being, functional well-being, and BC subscale were all identified to be associated with OS, PFS, and grade ≥3 adverse events (P < 0.05). Patient-reported physical well-being was the most prognostic PRO for all assessed outcomes. The OS prognostic performance of physical well-being (c = 0.58) was superior to ECOG PS (c = 0.56) (P < 0.05), with multivariable analysis indicating that both provide independent information (P < 0.0001). CONCLUSIONS: PROs were identified as independent prognostic factors for OS, PFS, and grade ≥3 adverse events in patients with human epidermal growth factor receptor 2 (HER2)-positive advanced BC initiating contemporary treatment options. Further, patient-reported physical well-being was more prognostic of OS than ECOG PS and contained independent information. PROs have value as prognostic and stratification factors for clinical use and research trials of anticancer treatment in HER2-positive ABC.

Clustering of comorbidities and associated outcomes in people with osteoarthritis - A UK Clinical Practice Research Datalink study.

OBJECTIVE: To examine the clusters of chronic conditions present in people with osteoarthritis and the associated risk factors and health outcomes. METHODS: Clinical Practice Research Datalink (CPRD) GOLD was used to identify people diagnosed with incident osteoarthritis (n = 221,807) between 1997 and 2017 and age (±2 years), gender, and practice matched controls (no osteoarthritis, n = 221,807) from UK primary care. Clustering of people was examined for 49 conditions using latent class analysis. The associations between cluster membership and covariates were quantified by odds ratios (OR) using multinomial logistic regression. General practice (GP) consultations, hospitalisations, and all-cause mortality rates were compared across the clusters identified at the time of first diagnosis of osteoarthritis (index date). RESULTS: In both groups, conditions largely grouped around five clusters: relatively healthy; cardiovascular (CV), musculoskeletal-mental health (MSK-MH), CV-musculoskeletal (CV-MSK) and metabolic (MB). In the osteoarthritis group, compared to the relatively healthy cluster, strong associations were seen for 1) age with all clusters; 2) women with the MB cluster (OR 5.55: 5.14-5.99); 3) obesity with the CV-MSK (OR 2.11: 2.03-2.20) and CV clusters (OR 2.03: 1.97-2.09). The CV-MSK cluster in the osteoarthritis group had the highest number of GP consultations and hospitalisations, and the mortality risk was 2.45 (2.33-2.58) times higher compared to the relatively healthy cluster. CONCLUSIONS: Of the five identified clusters, CV-MSK, CV, and MSK-MH are more common in OA and CV-MSK cluster had higher health utilisation. Further research is warranted to better understand the mechanistic pathways and clinical implications.

Synovitis and bone marrow lesions associate with symptoms and radiographic progression in hand osteoarthritis: a systematic review and meta-analysis of observational studies.

AIMS: To systematically review observational studies for the association between features detected on ultrasound (US) and magnetic resonance imaging (MRI) and, symptoms, signs and radiographic progression of hand osteoarthritis (OA). METHODS: Medline, Web of Science, EMBASE, CINAHL and AMED were searched from inception to 14th January 2020 to identify relevant studies. Quality of studies was assessed using the Newcastle-Ottawa scales and data were extracted. Odds ratios (OR) and linear regression coefficients and 95% confidence intervals (CI) were pooled using the random-effects model (METAN package, Stata v16.1). Heterogeneity and publication bias were assessed. RESULTS: Thirty-two studies using US and MRI comprising 1,350 and 638 participants respectively were included. While only grey-scale synovitis (GSS) associated with AUSCAN-pain (pooled Regression coefficient (95% CI): 0.46 (0.13-0.79); 0-20 scale for AUSCAN-pain), US-detected osteophytes, GSS and power Doppler (PD) [pooled ORs (95% CI): 2.68(2.16-3.33), 2.38(1.74-3.26) and 2.04 (1.45-2.88)] as well as MRI-detected bone marrow lesions (BMLs), synovitis, osteophytes, and central bone erosions (CBEs) associated with joint tenderness [pooled ORs (95% CI): 2.59(2.12-3.18), 2.17(1.85-2.54), 2.15(1.55-2.99), and 2.41 (1.45-4.02)] respectively. US-detected GSS and PD associated with radiographic progression of CBEs [pooled ORs 5.37, 5.08], osteophytes [pooled ORs 5.17, 6.45], and joint space narrowing (pooled ORs 4.28, 4.36) whilst MRI-detected synovitis and BMLs associated with increasing KL grades with pooled ORs 2.92, 2.54 respectively. CONCLUSIONS: US and MRI-detected structural and inflammatory changes associate with tenderness, whilst articular inflammation and subchondral bone damage associate with radiographic hand OA progression. There was inconsistent relationship between these changes and pain.

Distinguishing three Dragon fruit (Hylocereus spp.) species grown in Andaman and Nicobar Islands of India using morphological, biochemical and molecular traits.

Dragon fruit (Hylocereus spp.), an important tropical fruit belonging to the family Cactaceae, is rich in essential nutrients such as vitamins, minerals, complex carbohydrates, dietary fibres and antioxidants. This study aims to distinguish three dragon fruit species well adapted to Andaman and Nicobar Island through morphological (34 quantitative and 26 qualitative traits), biochemical (5 traits) and molecular (14 ISSR primers) characterization. Morphological characterization revealed that presence of considerable amount of genetic variations among them especially for fruit characters viz., colour of peel and pulp. Cladode characters such as number of spines (3-5), length of areoles (mm) as 1-4, margin ribs of cladode (convex or concave) and its waxiness (weak or strong white waxy or light waxy) could be used for identification of three Hylocereus spp. under present study. Highest co-efficient of variation (%) obtained for pulp weight (88.7), whereas, lowest in distance of anthers belowstigma (3.3). Fruit and pulp weight (g) ranged from 26.5-419.3 and 10.3-258.8 with mean value of 204.8 and 125.3, respectively. Comparatively, high phenol (71.3-161.3) and flavonoid (26.6-508.2) content observed in peels than pulp (32.5-130.0 and 45.0-258.2) of fruit indicating higher antioxidant potential. Highest total carotenoids (µg 100 g-1), ß-carotene (µg 100 g-1) and xanthophyll (µg g-1) content obtained in pulp on DGF3 (33.8), DGF4 (55.9) and DGF3 (32.7), whereas, in peel on DGF2 (24.3), DGF4 (18.5) and DGF2 (24.1), respectively. DPPH-based scavenging activity (%) revealed higher scavenging activity of peels (55.6-81.2) than pulp (36.0-75.3) extracts. Comparatively, ABTS-based scavenging activity (%) was found more than DPPH-based one. Sixteen ISSR primers screened, 14 were produced 178 reproducible amplified bands. Number of amplified bands varied from 5 in UBC887 to 19 in UBC811 with an average of 12.71 bands per primer. Range of polymorphic bands and % polymorphism observed were 1-13 and 20.0-92.8, respectively. The polymorphic information content value of ISSR marker ranged from 0.42 (UBC895) to 0.91 (UBC 856). Cluster analysis distinguished three different Hylocereus species on the basis of geographic origin and pulp colour by forming separate groups and two genotypes each showed 52% (DGF1 and DGF3) and 76% (DGF2 and DGF4) genetic similarity. Key traits identified for distinguishing three different Hylocereus species were: Pulp/ peel colour of fruits, number of spines and length of areoles in cladode. Genotypes with high carotenoid and xanthophylls content (DGF4 and DGF2) identified under present study may be of industrial importance for development of nutraceutical products to meet out the vitamin-A deficiency among humans in tropical regions needed future focus.

Efficacy of group intervention on tobacco cessation among male employees in health-care setting: A randomized controlled trial.

BACKGROUND: The tobacco epidemic is one of the biggest public health threats the world has ever faced. World Health Organization has estimated that tobacco use (smoking and smokeless) is currently responsible for the death of about 7 million people across the world each year. The objective of the study was not only to find the effect of group intervention on tobacco cessation but also to describe certain epidemiological factors associated with tobacco cessation and make suitable recommendations to tackle this epidemic. METHODS: A randomized controlled trial was carried out among male employees who were tobacco users in health-care setting in Western Maharashtra. In the study, 60 subjects each in intervention and control arm were taken. Pretested validated questionnaires were used for the study. The intervention comprised of two sessions delivered 5 weeks apart. Control arm received self-help material (Booklet) immediately after baseline data collection. The outcomes were measured using structured interview schedule. The data were analyzed using SPSS, version 20. RESULTS: Overall, 13.3% of the study subjects had quit tobacco use post intervention. In the intervention group 21.7% of the participants had quit tobacco since past one month and 5% in the control group (relative risk (RR) = 4.33). Low to moderate nicotine dependence (p = 0.023, RR = 6.46) and stage of contemplation (p = 0.018) were found to be important predictors of abstinence. CONCLUSION: Community-based group intervention for tobacco cessation is the way forward to tackle the tobacco epidemic.

Trends in incidence and prevalence of osteoarthritis in the United Kingdom: findings from the Clinical Practice Research Datalink (CPRD).

OBJECTIVE: This study aimed to explore the incidence and prevalence of OA in the UK in 2017 and their trends from 1997 to 2017 using a large nationally representative primary care database. DESIGN: The UK Clinical Practice Research Datalink (CPRD) comprising data on nearly 17.5 million patients was used for the study. The incidence and prevalence of general practitioner diagnosed OA over a 20 years period (1997-2017) were estimated and age-sex and length of data contribution standardized using the 2017 CPRD population structure. Cohort effects were examined through Age-period-cohort analysis. RESULTS: During 1997-2017, there were 494,716 incident OA cases aged ≥20 years. The standardised incidence of any OA in 2017 was 6.8 per 1000 person-years (95% CI 6.7 to 6.9) and prevalence was 10.7% (95% CI 10.7-10.8%). Both incidence and prevalence were higher in women than men. The incidence of any-OA decreased gradually in the past 20 years at an annual rate of -1.6% (95%CI -2.0 to -1.1%), and the reduction speeded up for people born after 1960. The prevalence of any-OA increased gradually at an annual rate of 1.4% (95% CI 1.3-1.6%). Although the prevalence was highest in Scotland and Northern Ireland, incidence was highest in the East Midlands. Both incidence and prevalence reported highest in the knee followed by hip, wrist/hand and ankle/foot. CONCLUSION: In the UK approximately one in 10 adults have symptomatic clinically diagnosed OA, the knee being the commonest. While prevalence has increased and become static after 2008, incidence is slowly declining. Further research is required to understand these changes.

Avoiding over- and undertreatment in patients with resected node-positive breast cancer with the use of gene expression signatures: are we there yet?

Prediction of benefit from adjuvant chemotherapy following resection of early breast cancer and, as a result, proper selection of candidates remains an elusive goal since the relative magnitude of benefit is the same regardless of the presence of clinicopathologic factors. Multiple studies, including randomized trials, establish the role of certain gene expression signatures in node-negative disease since they predict the risk of breast cancer relapse being so low that adjuvant chemotherapy can be omitted. In contrast, more limited data are available in higher risk, node-positive breast cancer patients, making the exclusion of adjuvant chemotherapy potentially hazardous. 'Prospective-retrospective' studies and limited prospective data show that several signatures, namely Oncotype Dx, MammaPrint, Prosigna, EndoPredict and Breast Cancer Index, select with different levels of success node-positive patients at very low risk for distant recurrence despite not receiving chemotherapy, although the long-term follow-up is still awaited. Pending, however the publication of the results from ongoing randomized studies which enroll patients with node-positive disease, major caution is warranted. Improper use and misinterpretation of these transcriptomic profiles can lead to undertreatment and exposure of patients to unnecessary risks resulting in increased breast cancer mortality for patients with axillary node-positive disease. With this review we critically discuss the available data on gene expression signatures that are used in clinical practice and offer practical recommendations regarding the management of patients with ER-positive, human epidermal growth factor receptor 2 (HER2)-negative, node-positive breast cancer.

Prospective evaluation of the cardiac safety of HER2-targeted therapies in patients with HER2-positive breast cancer and compromised heart function: the SAFE-HEaRt study.

PURPOSE: HER2-targeted therapies have substantially improved the outcome of patients with breast cancer, however, they can be associated with cardiac toxicity. Guidelines recommend holding HER2-targeted therapies until resolution of cardiac dysfunction. SAFE-HEaRt is the first trial that prospectively tests whether these therapies can be safely administered without interruptions in patients with cardiac dysfunction. METHODS: Patients with stage I-IV HER2-positive breast cancer candidates for trastuzumab, pertuzumab or ado-trastuzumab emtansine (TDM-1), with left ventricular ejection fraction (LVEF) 40-49% and no symptoms of heart failure (HF) were enrolled. All patients underwent cardiology visits, serial echocardiograms and received beta blockers and ACE inhibitors unless contraindicated. The primary endpoint was completion of the planned HER2-targeted therapies without developing either a cardiac event (CE) defined as HF, myocardial infarction, arrhythmia or cardiac death or significant asymptomatic worsening of LVEF. The study was considered successful if planned oncology therapy completion rate was at least 30%. RESULTS: Of 31 enrolled patients, 30 were evaluable. Fifteen patients were treated with trastuzumab, 14 with trastuzumab and pertuzumab, and 2 with TDM-1. Mean LVEF was 45% at baseline and 46% at the end of treatment. Twenty-seven patients (90%) completed the planned HER2-targeted therapies. Two patients experienced a CE and 1 had an asymptomatic worsening of LVEF to ≤ 35%. CONCLUSION: This study provides safety data of HER2-targeted therapies in patients with breast cancer and reduced LVEF while receiving cardioprotective medications and close cardiac monitoring. Our results demonstrate the importance of collaboration between cardiology and oncology providers to allow for delivery of optimal oncologic care to this unique population.

Integrating a newly developed BAC-based physical mapping resource for Lolium perenne with a genome-wide association study across a L. perenne European ecotype collection identifies genomic contexts associated with agriculturally important traits.

BACKGROUND AND AIMS: Lolium perenne (perennial ryegrass) is the most widely cultivated forage and amenity grass species in temperate areas worldwide and there is a need to understand the genetic architectures of key agricultural traits and crop characteristics that deliver wider environmental services. Our aim was to identify genomic regions associated with agriculturally important traits by integrating a bacterial artificial chromosome (BAC)-based physical map with a genome-wide association study (GWAS). METHODS: BAC-based physical maps for L. perenne were constructed from ~212 000 high-information-content fingerprints using Fingerprint Contig and Linear Topology Contig software. BAC clones were associated with both BAC-end sequences and a partial minimum tiling path sequence. A panel of 716 L. perenne diploid genotypes from 90 European accessions was assessed in the field over 2 years, and genotyped using a Lolium Infinium SNP array. The GWAS was carried out using a linear mixed model implemented in TASSEL, and extended genomic regions associated with significant markers were identified through integration with the physical map. KEY RESULTS: Between ~3600 and 7500 physical map contigs were derived, depending on the software and probability thresholds used, and integrated with ~35 k sequenced BAC clones to develop a resource predicted to span the majority of the L. perenne genome. From the GWAS, eight different loci were significantly associated with heading date, plant width, plant biomass and water-soluble carbohydrate accumulation, seven of which could be associated with physical map contigs. This allowed the identification of a number of candidate genes. CONCLUSIONS: Combining the physical mapping resource with the GWAS has allowed us to extend the search for candidate genes across larger regions of the L. perenne genome and identified a number of interesting gene model annotations. These physical maps will aid in validating future sequence-based assemblies of the L. perenne genome.

Mechanical, degradation and drug-release behavior of nano-grained Fe-Ag composites for biomedical applications.

An original fabrication route of high-strength bulk Fe-5Ag and Fe-10Ag nanocomposites with enhanced degradation rate is reported. Near fully dense materials with fine nanostructures and uniform distribution of Ag nanoparticles were obtained employing high energy attrition milling of Fe-Ag2O powder blends followed by cold sintering - high pressure consolidation at ambient temperature that allowed the retention of the nanoscale structure. Annealing in hydrogen flow at 550 °C resulted in enhanced ductility without coarsening the nanostructure. The strength in compression of Fe5Ag and Fe10Ag nanocomposites was several-fold higher than the values reported for similar composites with micrometer grain size. The galvanic action of finely dispersed Ag nanoparticles greatly increased the corrosion rate and degradation kinetics of iron. Following four weeks immersion of Fe-Ag nanocomposites in saline solution, a more than 10% weight loss accompanied by less than 25% decrease in bending strength were measured. The interconnected nanoporosity of cold sintered Fe-Ag nanocomposites was utilized for incorporation of vancomycin that was gradually released upon immersion. In cell culture experiments, the Fe-Ag nanocomposites supported the attachment of osteoblast cells and exhibited no signs of cytotoxicity. The results suggest that the proposed Fe-Ag nanocomposites could be developed into attractive biodegradable load-bearing implant materials with drug delivery capability.

Non-sinonasal isolated facio-orbital mucormycosis - A case report.

Mucormycosis is a rare clinical entity, often affect immunocompromised patients. It is an emergency situation and has poor prognosis. Prompt diagnosis with tissue biopsy, local control of the disease by aggressive surgical debridement and appropriate systemic antifungal treatment improve the prognosis and survival of the patients. Treatment of mucormycosis needs antifungal agents such as Amphotericin B and wide surgical debridement. Early diagnosis and treatment is often needed for survival of the patients. We describe a rare case of mucormycosis affecting facio-orbital area without involving sinon-nasal cavity.

Povidone iodine soaked gelfoam for the treatment of recalcitrant otomycosis - Our experiences at a tertiary care teaching hospital of eastern India.

INTRODUCTION: Otomycosis is a common clinical condition seen in outpatient department of otorhinolaryngology. The treatment of the otomycosis is also very simple. However, sometime it is difficult to treat otomycosis along with mastoid cavity, chronic suppurative otitis media, immunocompromised patient, etc. with conventional treatment, called recalcitrant otomycosis. Here, we describe a technique of treatment for recalcitrant otomycosis. MATERIALS AND METHODS: This is a prospective observational study/clinical trial carried out on 44 patients of recalcitrant otomycosis. They are divided into two groups, each of 22. One group treated with routine clotrimazole topical eardrops whereas other group treated with povidone iodine soaked gelfoam, placed in the external auditory canal. RESULTS: There was no significance difference according to the age (P=0.134), gender (P=0.760) and causative agents (P=0.750) between treatment groups. The resolution of the symptoms showed statistically significant on itching (P=0.0001), otorrhoea (P=0.0033), fullness (P=0.0432) and earache (P=0.0259), whereas no statistical significant on hearing loss (P=0.0683), when treating with povidone iodine soaked gelfoam as compared to routine (clotrimazole) treatment. Resolution of signs like canal wall erythema (P=0.0045), tragal tenderness (P=0.0012) and congestion of tympanic membrane (P=0.0088) is statistically significant when comparing clotrimazole with povidone iodine. Apart from these, we did not reveal any adverse effects from the study populations treated with povidone iodine soaked gelfoam. CONCLUSION: Use of the povidone iodine soaked gelfoam at the external auditory canal in recalcitrant otomycosis is an effective and well-tolerated treatment.

IL-15 supports the generation of protective lung-resident memory CD4 T cells.

Tissue-resident memory T cells (TRM) provide optimal defense at the sites of infection, but signals regulating their development are unclear, especially for CD4 T cells. Here we identify two distinct pathways that lead to the generation of CD4 TRM in the lungs following influenza infection. The TRM are transcriptionally distinct from conventional memory CD4 T cells and share a gene signature with CD8 TRM. The CD4 TRM are superior cytokine producers compared with conventional memory cells, can protect otherwise naive mice against a lethal influenza challenge, and display functional specialization by inducing enhanced inflammatory responses from dendritic cells compared with conventional memory cells. Finally, we demonstrate than an interleukin (IL)-2-dependent and a novel IL-2-independent but IL-15-dependent pathway support the generation of cohorts of lung TRM.