The G1-S checkpoint of the cell cycle is frequently dysregulated in breast cancer. Palbociclib (PD0332991) is an oral inhibitor of CDK4/6. Based upon preclinical/phase I activity, we performed a ...phase II, single-arm trial of palbociclib in advanced breast cancer.
Eligible patients had histologically confirmed, metastatic breast cancer positive for retinoblastoma (Rb) protein and measureable disease. Palbociclib was given at 125 mg orally on days 1 to 21 of a 28-day cycle. Primary objectives were tumor response and tolerability. Secondary objectives included progression-free survival (PFS) and assessment of Rb expression/localization, KI-67, p16 loss, and CCND1 amplification.
Thirty-seven patients were enrolled; 84% hormone-receptor (HR)(+)/Her2(-), 5% HR(+)/Her2(+), and 11% HR(-)/Her2(-), with a median of 2 prior cytotoxic regimens. Two patients had partial response (PR) and 5 had stable disease ≥ 6 months for a clinical benefit rate (CBR = PR + 6moSD) of 19% overall, 21% in HR(+), and 29% in HR(+)/Her2(-) who had progressed through ≥2 prior lines of hormonal therapy. Median PFS overall was 3.7 months 95% confidence interval (CI), 1.9-5.1, but significantly longer for those with HR(+) versus HR(-) disease (P = 0.03) and those who had previously progressed through endocrine therapy for advanced disease (P = 0.02). Grade 3/4 toxicities included neutropenia (51%), anemia (5%), and thrombocytopenia (22%). Twenty-four percent had treatment interruption and 51% had dose reduction, all for cytopenias. No biomarker identified a sensitive tumor population.
Single-agent palbociclib is well tolerated and active in patients with endocrine-resistant, HR(+), Rb-positive breast cancer. Cytopenias were uncomplicated and easily managed with dose reduction.
Allograft rejection is a serious concern in heart transplant medicine. Though endomyocardial biopsy with histological grading is the diagnostic standard for rejection, poor inter-pathologist ...agreement creates significant clinical uncertainty. The aim of this investigation is to demonstrate that cellular rejection grades generated via computational histological analysis are on-par with those provided by expert pathologists.
The study cohort consisted of 2472 endomyocardial biopsy slides originating from three major US transplant centres. The 'Computer-Assisted Cardiac Histologic Evaluation (CACHE)-Grader' pipeline was trained using an interpretable, biologically inspired, 'hand-crafted' feature extraction approach. From a menu of 154 quantitative histological features relating the density and orientation of lymphocytes, myocytes, and stroma, a model was developed to reproduce the 4-grade clinical standard for cellular rejection diagnosis. CACHE-grader interpretations were compared with independent pathologists and the 'grade of record', testing for non-inferiority (δ = 6%). Study pathologists achieved a 60.7% agreement 95% confidence interval (CI): 55.2-66.0% with the grade of record, and pair-wise agreement among all human graders was 61.5% (95% CI: 57.0-65.8%). The CACHE-Grader met the threshold for non-inferiority, achieving a 65.9% agreement (95% CI: 63.4-68.3%) with the grade of record and a 62.6% agreement (95% CI: 60.3-64.8%) with all human graders. The CACHE-Grader demonstrated nearly identical performance in internal and external validation sets (66.1% vs. 65.8%), resilience to inter-centre variations in tissue processing/digitization, and superior sensitivity for high-grade rejection (74.4% vs. 39.5%, P < 0.001).
These results show that the CACHE-grader pipeline, derived using intuitive morphological features, can provide expert-quality rejection grading, performing within the range of inter-grader variability seen among human pathologists.
: Knowledge of therapeutic lifestyle interventions is one of the most important pillars of diabetes care; however, its incorporation in real-world settings is poor. This review evaluates the role of ...partner and family support in diabetes management.
: Literature searches were performed in PubMed, Medline and Embase for articles published before July 2018, using the terms "therapeutic lifestyle intervention" MeSH Terms, OR "diet changes" All Fields, OR "spousal participation" All Fields, OR "lifestyle interventions" All Fields, "lifestyle changes" All Fields AND "diabetes" All Fields. The search was not restricted to English-language literature; literature in Spanish, French and German were also evaluated.
: A total of 66 of articles were reviewed, which included 33 original work, 21 review articles, and 12 systematic reviews and meta-analyses. Studies and meta-analyses have showed that if one partner has type-2 diabetes this increases the risk in other by 5-26%. Partner and family have similar diet, lifestyle, and micro- and macro-environments which could explain the similar increased risk of diabetes and non-communicable diseases. Studies have consistently shown that spousal and family support plays a key role in overcoming negative behaviours and optimising behaviours in diabetes control. Partner support has major role in prevention and control of diabetes distress, associated depression, and medication non-compliance which have an adverse impact in glycaemic outcomes. These data are predominantly available from observational studies. There is paucity of data from interventional trials evaluating effects of family and spousal participation on health, glycaemic control and quality of life.
: The support of family and spouse/partner is beneficial to improve adherence to the lifestyle interventions and pharmacotherapy required to achieve optimum glycaemic control and avoid associated complications.
Alveolar soft-part sarcoma (ASPS) is a rare soft tissue tumor that primarily involves the extremities. We report a case of a 30-year-old never-smoker man who presented with hematuria, dysuria, and ...constipation at an outside hospital. He was diagnosed with and treated for multiple episodes of urinary tract infection. However, he continued to have voiding symptoms for which a cystoscopy was performed and revealed a bladder neck mass. He underwent transurethral resection of a bladder tumor and was diagnosed with muscle-invasive urothelial carcinoma, nested variant, at an outside hospital. Subsequent to this diagnosis he transferred his care to our center. In-house imaging revealed a large vascular mass involving the prostate and pushing against the bladder base. Prostate needle biopsies were performed and revealed an epithelioid neoplasm with a nested growth pattern composed of cells with a moderate amount of eosinophilic cytoplasm, mildly pleomorphic nuclei, and occasional prominent nucleoli. Since the findings were not classic for urothelial carcinoma or for prostate cancer, we included a wider differential of poorly differentiated carcinoma, sarcoma, and paraganglioma. A wide panel of keratin stains was negative, ETS (erythroblast transformation-specific)-related gene highlighted an extensive vascular network and neuroendocrine stains were all negative. A transcription factor E3 fluorescent in-situ hybridization was positive and subsequently, an ASPSCR1 gene rearrangement was demonstrated. The outside hospital transurethral resection of bladder tumor was obtained for review and the tumor was morphologically similar to that seen on the in-house prostate needle biopsies. Based on the above findings a final diagnosis of primary ASPS of the prostate with involvement of the bladder was made. The patient was later diagnosed with bilateral lung metastases. He was treated with pazopanib, radiation therapy, and cystoprostatectomy and is symptom-free on a 15-month follow-up.
Introduction: Owing to its uncertain and multiple possible etiologies, use of multiple empirical treatment regimens and possibility of spontaneous recovery, it becomes important to look for the ...possible prognostic factors affecting the outcome of sudden sensorineural hearing loss (SSNHL).
Material and methods: This prospective observational study was conducted with the primary aim of analyzing the role of various possible prognostic factors on the outcome of idiopathic SSNHL including demographic (Age, gender), audio-vestibular (Pre-treatment hearing loss in the affected ear, hearing in the contralateral ear, time elapse between onset of hearing loss and start of treatment, type of hearing loss in term of frequencies affected), presence of tinnitus / vertigo and Comorbidities (Diabetes, Hypothyroidism & Deranged lipid profile/ dyslipidemia).
Result: The absence of vertigo and tinnitus led to better hearing outcomes while raised HbA1c levels, deranged lipids and thyroid profiles adversely affected the outcome.
Conclusion: Vertigo, tinnitus, raised HbA1c levels, deranged lipids and thyroid profiles are possible negative prognostic factors. Better pretreatment hearing levels in the affected and unaffected ears prompted improved recovery.
Objective
To externally validate a Genomic Classifier (GC) based risk-stratification nomogram identifying candidates who would benefit from adjuvant radiation (aRT) therapy after radical ...prostatectomy (RP).
Methods
We identified 350 patients who underwent RP, between 2013 and 2018, and had adverse pathological features (positive margin, and/or pT3a or higher) on final pathology. Genomic profile was available for all these men. The clinical recurrence-free survival was estimated using the Kaplan–Meier method. The external validity of the nomogram was tested using the concordance index (c-index), calibration plot, and decision curve analysis.
Results
The median follow-up of the cohort was 26.5 months. Overall, 14% of the patients received aRT. During the follow-up period, 3.4% of the patients developed metastasis. Overall 3-year metastasis-free survival was 95% (95% CI 0.92–0.98). The c-index of the nomogram was 0.84. The calibration of the model was favorable. Decision-curve analysis showed a positive net benefit for probabilities ranging between 0.01 and 0.09, with the highest difference at threshold probability around 0.05. At that threshold, the net benefit is 0.06 for the model and 0 for treating all the patients.
Conclusion
Our report is the first to confirm the validity of this genomic-based risk-stratification tool in identifying men who might benefit from aRT after RP. As such, it can be a useful instrument to be incorporated in shared decision making on whether administration of aRT will lead to a clinically meaningful benefit. Such a model can also be useful for patients’ classification in future clinical trials.
Lamin A/C (LMNA) gene mutations cause a heterogeneous group of progeroid disorders, including Hutchinson-Gilford progeria syndrome, mandibuloacral dysplasia, and atypical progeroid syndrome (APS). ...Five of the 31 previously reported patients with APS harbored a recurrent de novo heterozygous LMNA p.T10I mutation. All five had generalized lipodystrophy, as well as similar metabolic and clinical features, suggesting a distinct progeroid syndrome.
We report nine new patients and follow-up of two previously reported patients with the heterozygous LMNA p.T10I mutation and compare their clinical and metabolic features with other patients with APS.
Compared with other patients with APS, those with the heterozygous LMNA p.T10I mutation were younger in age but had increased prevalence of generalized lipodystrophy, diabetes mellitus, acanthosis nigricans, hypertriglyceridemia, and hepatomegaly, together with higher fasting serum insulin and triglyceride levels and lower serum leptin and high-density lipoprotein cholesterol levels. Prominent clinical features included mottled skin pigmentation, joint contractures, and cardiomyopathy resulting in cardiac transplants in three patients at ages 13, 33, and 47 years. Seven patients received metreleptin therapy for 0.5 to 16 years with all, except one noncompliant patient, showing marked improvement in metabolic complications.
Patients with the heterozygous LMNA p.T10I mutation have distinct clinical features and significantly worse metabolic complications compared with other patients with APS as well as patients with Hutchinson-Gilford progeria syndrome. We propose that they be recognized as having generalized lipodystrophy-associated progeroid syndrome. Patients with generalized lipodystrophy-associated progeroid syndrome should undergo careful multisystem assessment at onset and yearly metabolic and cardiac evaluation, as hyperglycemia, hypertriglyceridemia, hepatic steatosis, and cardiomyopathy are the major contributors to morbidity and mortality.
The Twin White Herrings: Salt and Sugar Gupta, Lovely; Khandelwal, Deepak; Dutta, Deep ...
Indian journal of endocrinology and metabolism,
07/2018, Letnik:
22, Številka:
4
Journal Article
Recenzirano
Odprti dostop
India has the dubious distinction of being a hotspot for both diabetes and hypertension. Increased salt and sugar consumption is believed to fuel these two epidemics. This review is an in-depth ...analysis of current medical literature on salt and sugar being the two white troublemakers of modern society. The PubMed, Medline, and Embase search for articles published in January 2018, using the terms "salt" MeSH Terms OR "sodium chloride" All Fields OR "sugar" All Fields. India is world's highest consumer of sugar with one of the highest salt consumption per day. Increased salt intake is associated with increased risk of hypertension, left ventricular hypertrophy and fibrosis, cardiovascular events, renal stones, proteinuria, and renal failure. Increased sugar intake is directly linked to increased risk of obesity, fatty liver disease, and metabolic syndrome. Also, increased sugar intake may be indirectly related to the increased risk of type 2 diabetes. Both salt and sugar intake is directly linked to increased systemic and hypothalamic inflammation, endothelial dysfunction, microangiopathy, cardiovascular remodelling, cancers, and death. High fructose corn is especially damaging. There is no safe limit of sugar consumption, as the human body can produce its own glucose. Being nature's gift to mankind, there is no harm in moderate consumption of salt and sugar, however, modest reduction in the consumption of both can substantially reduce the burden of non-communicable diseases. Public health interventions to facilitate this behavioural change must be instituted and encouraged.
High burden of anaemia exists amongst rural adolescent girls in India. The objective of this study was to characterise anaemia in school going adolescent girls in rural Haryana, India.
Linear and ...multiple logistic regression analysis of data collected prior to an intervention trial was conducted. Participants were classified into anaemic (haemoglobin <12 g/dl) and non-anaemic group and were further classified into deficiencies of Fe, folate or vitamin B12, mixed, anaemia of other causes and inflammation.
Three schools in Ballabgarh block of Faridabad District, Haryana, India.
One hundered and ninety-eight non-anaemic and 202 anaemic adolescent girls (12-19 years).
Anaemic girls had 29·6 % Fe deficiency, 28·1 % folate or vitamin B12 deficiency, 15·8 % mixed deficiency and 9·7 % acute inflammation. Anaemia of other causes was found in 16·8 % of the anaemic participants. Girls with Fe and isolated folate deficiency had 2·5 times and four times higher odds of developing anaemia, respectively, as compared with non-anaemic girls. Fe deficiency with no anaemia was found amongst 11 % non-anaemic girls. Non-anaemic girls had a high prevalence of combined deficiency of folate or vitamin B12 (29·5 %) and acute inflammation (14·4 %).
The current strategy of Fe and folic acid supplementation alone will not suffice for achieving the desired reduction in the prevalence of anaemia as unknown causes and anaemia of inflammation contribute to a substantial proportion of anaemia. Integrating other nutrition-specific components like improving water, sanitation and hygiene practices with the ongoing micronutrient supplementation program will comprehensively tackle anaemia. Unknown causes of anaemia warrant further research.
Obesity reflects a chronic inflammatory environment that may contribute to prostate cancer progression and poor treatment outcomes. However, it is not clear which mechanisms drive this association ...within the tumor microenvironment. The aim of this pilot study was to examine prostatic inflammation via tumor infiltrating lymphocytes and macrophages characterized by obesity and cancer severity.
We studied paraffin-embedded prostatectomy tissue from 99 participants (63 non-obese and 36 obese) from the Study of Clinical Outcomes, Risk and Ethnicity (University of Pennsylvania). Pathologists analyzed the tissue for type and count of lymphocytes and macrophages, including CD3, CD8, FOXP3, and CD68. Pathology data were linked to clinical and demographic variables. Statistical analyses included frequency tables, Kruskal-Wallis tests, Spearman correlations, and multivariable models.
We observed positive univariate associations between the number of CD68 cells and tumor grade (p = 0.019). In multivariable analysis, CD8 counts were associated with time to biochemical failure (HR = 1.09, 95% CI = 1.004-1.192, p-value = 0.041.) There were no differences in lymphocytes or macrophages by obesity status or BMI.
The number of lymphocytes and macrophages in the tumor microenvironment did not differ by obesity status. However, these inflammation markers were associated with poor prostate cancer outcomes. Further examination of underlying mechanisms that influence obesity-related effects on prostate cancer outcomes is warranted. Such research will guide immunotherapy protocols and weight management as they apply to diverse patient populations and phenotypes.
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