Solid organ transplant (SOT) is frequently complicated by cancers, which render immunosuppression challenging. Immune checkpoint inhibitors have emerged as treatments for many cancers. Data are lacking regarding efficacy and rejection risk in the SOT population. We conducted a systematic literature review and analyzed 83 cases of immune checkpoint inhibitor use for cancer in SOT. Two thirds of these patients received anti–programmed death ligand 1 therapy, 15.7% received anti–cytotoxic T lymphocyte–associated protein 4 therapy, and 10.8% received a combination. Allograft rejection occurred in 39.8% of patients, leading to end‐stage organ failure in 71.0% of cases. Outcomes were similar across organs and immunotherapy regimens. The use of immunosuppressants other than steroids, time since transplant, and prior episodes of rejection were associated with the risk of rejection. The median overall survival of patients was 36 weeks. Most of the deaths were related to cancer progression. In nonkidney recipients, graft rejection was strongly associated with worse survival. At the end of the study, 19.3% of the patients were alive, free from rejection and tumor progression. This study highlights the difficult tradeoff facing oncologists and transplant specialists managing transplant recipients with cancer, and the need for prospective data and novel biomarkers for identifying the patients likely to benefit from immunotherapy in the SOT setting.

Dopamine (DA) neurons of the ventral tegmental area (VTA) integrate cholinergic inputs to regulate key functions such as motivation and goal-directed behaviors. Yet the temporal dynamic range and mechanism of action of acetylcholine (ACh) on the modulation of VTA circuits and reward-related behaviors are not known. Here, we used a chemical-genetic approach for rapid and precise optical manipulation of nicotinic neurotransmission in VTA neurons in living mice. We provide direct evidence that the ACh tone fine-tunes the firing properties of VTA DA neurons through β2-containing (β2*) nicotinic ACh receptors (nAChRs). Furthermore, locally photo-antagonizing these receptors in the VTA was sufficient to reversibly switch nicotine reinforcement on and off. By enabling control of nicotinic transmission in targeted brain circuits, this technology will help unravel the various physiological functions of nAChRs and may assist in the design of novel therapies relevant to neuropsychiatric disorders.

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SummaryDopamine (DA) neurons of the ventral tegmental area (VTA) integrate cholinergic inputs to regulate key functions such as motivation and goal-directed behaviors. Yet the temporal dynamic range and mechanism of action of acetylcholine (ACh) on the modulation of VTA circuits and reward-related behaviors are not known. Here we used a chemical-genetic approach for rapid and precise optical manipulation of nicotinic neurotransmission in VTA neurons in vivo. We provide direct evidence that the ACh tone fine-tunes the firing properties of VTA DA neurons through somatic b2-containing (b2*) nicotinic ACh receptors (nAChRs). Furthermore, locally photoantagonizing these receptors in the VTA was sufficient to reversibly switch nicotine reinforcement on and off. By enabling control of nicotinic transmission in targeted brain circuits, this technology will help unravel the various physiological functions of nAChRs and may assist in the design of novel therapies relevant to neuropsychiatric disorders. peer-reviewed)

Background and Aims Myeloproliferative neoplasms (MPN) are chronic blood disorders defined by an overproduction of clonal, differentiated hematopoietic cells. A high prevalence of chronic kidney disease (CKD) is described in patients with MPN. The glomerular histological pattern of MPN-related kidney disease, MPN-related glomerulopathy (MPN-RG), may not account for the entirety of CKD risk in this population, as it appears to be rare and has mostly been reported in patients with myelofibrosis. The inflammatory and prothrombotic state of clonal blood cells has been linked to a systemic vasculopathy in MPN patients, characterized by thromboses and microvascular disease. Thus, we put forward the hypothesis that intrarenal vessel injury may occur during MPN, and that vascular nephrosclerosis may be a common histological pattern in MPN patients presenting with kidney disease. Method We conducted an exhaustive, retrospective, multicenter study of MPN kidney biopsies in four kidney pathology units. All adult patients with a history of MPN who underwent a kidney biopsy were included. We performed a systematic histological review of glomerular and vascular compartments. MPN-RG was defined as mesangial expansion and negative glomerular immunofluorescence studies, with at least one of the following: mesangial hypercellularity, or features of chronic glomerular thrombotic microangiopathy. Hematopoietic cells were detected using anti-glycophorin C, anti-myeloperoxidase, and anti-factor VIII immunohistochemistry (IHC). Chronic vascular lesions were evaluated using the Banff aah and cv lesion definitions and compared to matched adult native kidney biopsies. We used multivariable logistic regression models to assess determinants of vascular lesions, using the number of antihypertensive drugs as a proxy for hypertension severity. Results We included 47 MPN patients who underwent a kidney biopsy, including 16 patients with chronic myeloid leukemia, 14 with polycythemia vera, 10 with essential thrombocythemia and 7 with primary myelofibrosis. 14 cases (29.8%) met our definition of MPN-RG. MPN-RG was strongly associated with myelofibrosis (primary or secondary, P = 0.021) and poorer ESRD-free survival (P = 0.007). Positive IHC for circulating cells in the glomerular capillaries was not associated with glomerular injury but was positively correlated with blood leukocyte count (P = 0.004). Thirty-three patients (75.0%) had moderate-to-severe arteriosclerosis; 39 patients (84.8%) had moderate-to-severe arteriolar hyalinosis. Multivariable models including 188 control kidney biopsies revealed an association between MPN and chronic kidney vascular damage, which was independent of established risk factors such as age, diabetes mellitus and hypertension (Table 1 and Table 2). Conclusion We demonstrate the strong association between MPN-RG and myelofibrosis and confirm its poor renal prognosis. We argue that the finding of glomerular intracapillary hematopoietic cells should not be considered in the diagnosis of MPN-RG. Most notably, our results show that MPN represent a novel, independent risk factor for vascular nephrosclerosis, and establish a new link between MPN and CKD. These findings raise new hypotheses regarding the pathophysiology of vascular nephrosclerosis in the general population.

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