Clonal replacement of tumor-specific T cells following PD-1 blockade.

Immunotherapies that block inhibitory checkpoint receptors on T cells have transformed the clinical care of patients with cancer1. However, whether the T cell response to checkpoint blockade relies on reinvigoration of pre-existing tumor-infiltrating lymphocytes or on recruitment of novel T cells remains unclear2-4. Here we performed paired single-cell RNA and T cell receptor sequencing on 79,046 cells from site-matched tumors from patients with basal or squamous cell carcinoma before and after anti-PD-1 therapy. Tracking T cell receptor clones and transcriptional phenotypes revealed coupling of tumor recognition, clonal expansion and T cell dysfunction marked by clonal expansion of CD8+CD39+ T cells, which co-expressed markers of chronic T cell activation and exhaustion. However, the expansion of T cell clones did not derive from pre-existing tumor-infiltrating T lymphocytes; instead, the expanded clones consisted of novel clonotypes that had not previously been observed in the same tumor. Clonal replacement of T cells was preferentially observed in exhausted CD8+ T cells and evident in patients with basal or squamous cell carcinoma. These results demonstrate that pre-existing tumor-specific T cells may have limited reinvigoration capacity, and that the T cell response to checkpoint blockade derives from a distinct repertoire of T cell clones that may have just recently entered the tumor.

Association of plasma des-acyl ghrelin levels with CKD.

BACKGROUND AND OBJECTIVES: There are no effective therapies for malnutrition in CKD/ESRD patients. This study hypothesized that ghrelin, an endogenous orexigenic hormone, would correlate with renal function and might suggest therapeutic interventions for CKD/ESRD malnutrition. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Fifty-one CKD and 15 hemodialysis patients were enrolled. Acyl ghrelin (AG) and des-acyl ghrelin (DG) were determined using separate two-site-specific assays. Leptin, insulin, growth hormone, insulin-link growth factor-1, C-reactive protein, TNF-α, and IL-6 were also measured. RESULTS: Univariate correlation analyses showed that CKD stage was highly, positively correlated with the levels of preprandial and postprandial DG and positively correlated with TNF-α, IL-6, leptin, and age. Multivariate partial-correlation analyses showed that CKD was independently associated with the proportion of preprandial and postprandial DG, whereas TNF-α, IL-6, leptin, insulin, and age were not independently associated with either. Geometric mean (GM) preprandial and postprandial AG were comparable between CKD stages ≤2 and >2, whereas GM preprandial DG and postprandial DG were 1.95-fold and 2.17-fold greater, respectively, for CKD stage >2 versus stage ≤2. DG was the dominant form of ghrelin preprandially and postprandially for both CKD stages ≤2 and >2. Dialysis had no effect on AG, but reduced DG by 73% to levels even lower (GM 48.7 pg/ml) than those seen postprandially in CKD stage ≤2 patients (GM 77.0 pg/ml). CONCLUSIONS: This study shows a strong and independent correlation of DG with CKD stage. Postprandial suppression of ghrelin is impaired with reduced renal function. Hemodialysis selectively removes DG but not AG.

Native renal biopsies: complications and glomerular yield between radiologists and nephrologists.

Kidney biopsies have been taken over by radiologists at many institutions. This tendency for radiology referral by nephrologists has two main drawbacks: 1) No follow-up care from the physician performing the procedure and 2) Loss of required procedure training for nephrology fellows. This study assesses for differences in glomerular yield and immediate procedure-related complications between radiology-performed (RP) and nephrology-performed (NP) percutaneous native kidney biopsies at our institution for an 11-month period. All biopsies were done with real time ultrasound guidance. Further analysis was done to look for any correlation between the number of needle insertions ("passes"), needle size and procedure-related complications (graded on a score from 0-4). A total of 37 native kidney biopsies were performed during the study period. Fourteen biopsies (38%) were performed by radiology while a nephrology fellow performed 23 biopsies (62%). The mean glomerular count for RP biopsies was 15+/-10 and for NP 16+/-11 (p=ns). The number of passes ranged from 1-5 in the RP group with a total of 33 passes in 14 patients (mean 2.36 passes/patient). Passes ranged from 1-6 in the NP group with 57 passes in 23 patients (mean 2.48 passes/patient). Mean complication scores were similar in both groups. However, severe complications (score 4) were significantly lower in nephrology fellow performed biopsies (p = 0.001). Despite similar pre-biopsy risk assessment and treatment protocols with real-time ultrasound guidance of all biopsies, these results show no statistically significant differences in glomerular yield or overall complication scores but did demonstrate a significantly higher rate of severe complications (score 4) in the RP performed biopsies. Nephrology fellows perform native kidney biopsies at a level equal to or superior to radiologists.

Asbestos in developing countries: magnitude of risk and its practical implications.

In developing countries, aggressive marketing of chrysotile asbestos continues as a result of restrictions on its use being imposed by the developed countries. In the Asian continent, China and India are emerging as the major users of asbestos. There is enough evidence to link chrysotile with pulmonary fibrosis and lung cancer in humans, even at low levels of exposure, hence the need to apply the Precautionary Principle for phasing out its use globally. Due to poor occupational health and safety systems in developing countries and difficulties in early detection of pulmonary malignancy related to asbestos, the statistics remain sketchy. This is hampering efforts to create pressure on policy makers and to counter the propaganda of the asbestos industry. The International Labour Office believes that more than 100,000 deaths a year occur from asbestos-related disease. In the view of studies published in Europe and Australia, the number of deaths due to such malignancies will peak around the year 2020 and could be anywhere between half a million to a million. That means more than a million deaths will occur in developing countries. At about the same time when asbestos-related deaths start to decrease in developed countries, their number will begin to rise in developing countries. This presents a major challenge to the international scientific community.

Asbestos-related morbidity in India.

In India, locally mined asbestos is not enough for its current needs, hence a great deal of asbestos is imported from Canada. Asbestos products manufacturers have prevailed upon the government to reduce tariffs on imported material. The efforts of the health and safety professionals who joined with nongovernmental organizations to form the Ban Asbestos Network of India (BANI) are being consistently sabotaged by the industry, using its influence and false propaganda that chrysotile asbestos can be safely used in a controlled manner. Weak legislation and lack of data are being exploited by the industry to convince policymakers that asbestos use in India has caused no major health problems. Despite this, the ban-asbestos movement has gained momentum and was able to persuade government to consider banning asbestos use. With the growing strength of the movement it is expected that asbestos manufacturers may find it increasingly difficult to manipulate the government in the future.

Takayasu arteritis presenting as a pulmonary-renal syndrome.

Takayasu arteritis is an uncommon disease with a variety of presentations. We report a case of Takayasu arteritis with a presentation of a pulmonary-renal syndrome in a 22-year-old woman. She presented in acute respiratory failure with hemoptysis and acute renal failure; interestingly, however, the renal biopsy was normal. Magnetic resonance angiography (MRA) showed significant narrowing in the distal abdominal aorta with bilateral renal and common iliac artery occlusions. Thoracic and abdominal angiogram confirmed MRA findings of type IV Takayasu arteritis. Percutaneous transluminal angioplasty of the left renal artery normalized kidney function. The initial presentation of Takayasu arteritis as a pulmonary-renal syndrome with severe acute renal failure and diffuse pulmonary hemorrhage is unusual; to our knowledge, this has not been described previously in the literature. We provide a clinical review of Takayasu arteritis and a discussion of systemic manifestations pertinent to the case.