Feasibility of whole genome and transcriptome profiling in pediatric and young adult cancers.

The utility of cancer whole genome and transcriptome sequencing (cWGTS) in oncology is increasingly recognized. However, implementation of cWGTS is challenged by the need to deliver results within clinically relevant timeframes, concerns about assay sensitivity, reporting and prioritization of findings. In a prospective research study we develop a workflow that reports comprehensive cWGTS results in 9 days. Comparison of cWGTS to diagnostic panel assays demonstrates the potential of cWGTS to capture all clinically reported mutations with comparable sensitivity in a single workflow. Benchmarking identifies a minimum of 80× as optimal depth for clinical WGS sequencing. Integration of germline, somatic DNA and RNA-seq data enable data-driven variant prioritization and reporting, with oncogenic findings reported in 54% more patients than standard of care. These results establish key technical considerations for the implementation of cWGTS as an integrated test in clinical oncology.

Commentary on "DNA damage response and repair gene alterations are associated with improved survival in patients with platinum-treated advanced urothelial carcinoma."

PURPOSE: Platinum-based chemotherapy remains the standard treatment for advanced urothelial carcinoma by inducing DNA damage. We hypothesize that somatic alterations in DNA damage response and repair (DDR) genes are associated with improved sensitivity to platinum-based chemotherapy. EXPERIMENTAL DESIGN: Patients with diagnosis of locally advanced and metastatic urothelial carcinoma treated with platinum-based chemotherapy who had exon sequencing with the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assay were identified. Patients were dichotomized based on the presence/absence of alterations in a panel of 34 DDR genes. DDR alteration status was correlated with clinical outcomes and disease features. RESULTS: One hundred patients were identified, of which 47 harbored alterations in DDR genes. Patients with DDR alterations had improved progression-free survival (9.3 vs. 6.0 months, log-rank P = 0.007) and overall survival (23.7 vs. 13.0 months, log-rank P = 0.006). DDR alterations were also associated with higher number mutations and copy-number alterations. A trend toward positive correlation between DDR status and nodal metastases and inverse correlation with visceral metastases were observed. Different DDR pathways also suggested variable effect on clinical outcomes. CONCLUSIONS: Somatic DDR alteration is associated with improved clinical outcomes in platinum-treated patients with advanced urothelial carcinoma. Once validated, it can improve patient selection for clinical practice and future study enrollment.

Reduction of Extended-Release Tacrolimus Dose in Low-Immunological-Risk Kidney Transplant Recipients Increases Risk of Rejection and Appearance of Donor-Specific Antibodies: A Randomized Study.

The aim of this study (ClinicalTrials.gov, NCT01744470) was to determine the efficacy and safety of two different doses of extended-release tacrolimus (TacER) in kidney transplant recipients (KTRs) between 4 and 12 mo after transplantation. Stable steroid-free KTRs were randomized (1:1) after 4 mo: Group A had a 50% reduction in TacER dose with a targeted TacER trough level (C0 ) >3 µg/L; group B had no change in TacER dose (TacER C0 7-12 µg/L). The primary outcome was estimated GFR at 1 year. Of 300 patients, the intent-to-treat analysis included 186 patients (group A, n = 87; group B, n = 99). TacER C0 was lower in group A than in group B at 6 mo (4.1 ± 2.7 vs. 6.7 ± 3.9 µg/L, p < 0.0001) and 12 mo (5.6 ± 2.0 vs. 7.4 ± 2.1 µg/L, p < 0.0001). Estimated GFR was similar in both groups at 12 mo (group A, 56.0 ± 17.5 mL/min per 1.73 m²; group B, 56.0 ± 22.1 mL/min per 1.73 m²). More rejection episodes occurred in group A than group B (11 vs. 3; p = 0.016). At 1 year, subclinical inflammation occurred more frequently in group A than group B (inflammation score [i] >0: 21.4% vs. 8.8%, p = 0.047; tubulitis score [t] >0: 19.6% vs. 8.7%, p = 0.076; i + t: 1.14 ± 1.21 vs. 0.72 ± 1.01, p = 0.038). Anti-HLA donor-specific antibodies appeared only in group A (6 vs. 0 patients, p = 0.008). TacER C0 should be maintained >7 µg/L during the first year after transplantation in low-immunological-risk, steroid-free KTRs receiving a moderate dose of mycophenolic acid.

Severe cryptococcal-associated neurological immune reconstitution inflammatory syndrome in a renal transplant recipient treated with adalimumab.

Cryptococcosis is a major concern in organ transplant recipients. A decrease in immunosuppressants following the initiation of antifungal therapy is currently recommended, but can occasionally be complicated by the onset of immune reconstitution inflammatory syndrome (IRIS). We report on a case of cryptococcosis in a kidney transplant recipient, compounded by severe neurological IRIS, the outcome of which was unfavorable despite the use of anti-tumor necrosis factor-alpha monoclonal antibodies.

[Renal lymphangiectasia, a rare case of perirenal infiltration]. / La lymphangiectasie rénale, un cas rare d'infiltration périrénale.

Renal lymphangiectasia is a bilateral cystic infiltration of the perirenal and parapelvic space which is caused by the obstruction of the renal lymphatic tissue. To our knowledge only numbers have been reported in the literature. Renal lymphangiectasia usually asymptomatic and incidentally diagnosed has absolutely no effect on the patient outcome. Radiological imaging is typical so that the diagnosis does not need to be confirmed by a cyst punction. The lack of knowledge concerning renal lymphangiectasia make it usually confused with another cause of polycystic renal infiltration, such as the polycystic kidney disease. We report herein a case of renal lymphangiectasia diagnosed incidentally by an abdominal ultrasonography.

Renal transplantation in patients with AA amyloidosis nephropathy: results from a French multicenter study.

Although end-stage renal disease related to AA amyloidosis nephropathy is well characterized, there are limited data concerning patient and graft outcome after renal transplantation. We performed a multicentric retrospective survey to assess the graft and patient survival in 59 renal recipients with AA amyloidosis. The recurrence rate of AA amyloidosis nephropathy was estimated at 14%. The overall, 5- and 10-year patient survival was significantly lower for the AA amyloidosis patients than for a control group of 177 renal transplant recipients (p = 0.0001, 0.028 and 0.013, respectively). In contrast, we did not observe any statistical differences in the 5- and 10- year graft survival censored for death between two groups. AA amyloidosis-transplanted patients exhibited a high proportion of infectious complications after transplantation (73.2%). Causes of death included both acute cardiovascular events and fatal septic complications. Multivariate analysis demonstrated that the recurrence of AA amyloidosis on the graft (adjusted OR = 14.4, p = 0.01) and older recipient age (adjusted OR for a 1-year increase = 1.06, p = 0.03) were significantly associated with risk of death. Finally, patients with AA amyloidosis nephropathy are eligible for renal transplantation but require careful management of both cardiovascular and infectious complications to reduce the high risk of mortality.

Metabolic stress promotes renal tubular inflammation by triggering the unfolded protein response.

The renal epithelium contributes to the development of inflammation during ischemic injury. Ischemia induces endoplasmic reticulum (ER) stress and activates the unfolded protein response (UPR). Ischemic tissues generate distress signals and inflammation that activates fibrogenesis and may promote adaptive immunity. Interestingly, the UPR may activate inflammation pathways. Our aim was to test whether the UPR is activated during metabolic stress and mediates a tubular inflammatory response. Glucose deprivation, not hypoxia and amino acids deprivation, activated the UPR in human renal cortical tubular cells in culture. This stress activated NF-κB and promoted the transcription of proinflammatory cytokines and chemokines, including IL-6, IL-8, TNF-α, RANTES and MCP-1. The protein kinase RNA (PKR)-like ER kinase signaling pathway was not required for the induction of inflammation but amplified cytokine. Inositol-requiring enzyme 1 activated NF-κB signaling and was required for the transcription of proinflammatory cytokines and chemokines following metabolic stress. Moreover, acute ischemia activated ER stress and inflammation in rat kidneys. Finally, the ER stress marker GRP78 and NF-κB p65/RelA were coexpressed in human kidney transplants biopsies performed before implantation, suggesting that ER stress activates tubular inflammation in human renal allografts. In conclusion, this study establishes a link between ischemic stress, the activation of the UPR and the generation of a tubular inflammatory response.

Cyclosporine-induced endoplasmic reticulum stress triggers tubular phenotypic changes and death.

The molecular mechanisms by which cyclosporine induces chronic nephrotoxicity remain poorly understood. A previous transcriptomic study suggested that cyclosporine might induce endoplasmic reticulum (ER) stress in human tubular cells. The aim of the present study was to characterize the features of tubular ER stress induced by cyclosporine and to investigate its effects on cell differentiation and viability. Using primary cultures of human tubular cells, we confirmed that cyclosporine is responsible for ER stress in vitro. This was also confirmed in vivo in the rat. In vitro, cyclosporine and other ER stress inducers were responsible for epithelial phenotypic changes leading to the generation of protomyofibroblasts, independent of transforming growth factor-beta signaling. RNA interference directed against cyclophilin A supported the role of its inhibition in triggering ER stress as well as epithelial phenotypic changes induced by cyclosporine. Salubrinal, which is known to protect cells from ER stress, significantly reduced epithelial phenotypic changes and cytotoxicity induced by cyclosporine in vitro. Salubrinal also reduced cyclosporine nephrotoxicity in rat kidneys. Thus, we describe a novel mechanism that initiates dedifferentiation and tubular cell death upon cyclosporine treatment. These results provide an interesting framework for further nephroprotective therapies by targeting ER stress.

[Primitive metastasizing bronchial carcinoid with long survival]. / Carcinoïde bronchique d'emblée multimétastatique et survie prolongée. Une entité anatomo-clinique peu connue: place de l'imagerie fonctionnelle.

BACKGROUND: Metastatic bronchial carcinoid tumours are rare but some patients have a prolonged survival. A new functional imagery now makes it possible to supplement the assessment of the extent of disease. OBSERVATION: A 57 year old patient was referred for dyspnoea on exertion revealing an upper left lobar tumour, with carcinoid syndrome. The assessment enabled to find out a bronchial carcinoid tumour with liver and bone metastases, highlighted by positron-emission tomography and pentetreotide SPECT. A chemotherapy proved to be ineffective and upper left lobectomy was carried out because of the risk of pulmonary atelectasis. The patient was treated by somatostatin analogues then underwent liver transcatheter arterial chemo-embolization. The patient was alive 44 months after diagnosis (56 months after first computed tomography). CONCLUSION: Metastatic bronchial carcinoid tumours are rare. They keep a metastatic potential, the histological type remaining the major prognosis factor. Carcinoid syndrome is suggestive. The assessment of extra-thoracic disease extent benefits by contribution of new functional imagery techniques such as the pentetreotide SPECT and positron-emission tomography. The management is essentially symptomatic since there is no effective chemotherapy. However survival can be prolonged, even in multimetastatic patients.

[Iatrogenic risk of self-medication by the pregnant patient]. / Risques iatrogènes de l'automédication chez la femme enceinte.

REALITY OF SELF-MEDICATION IN PREGNANCY: Pregnant women use self-medication readily. Such behavior must not be overlooked by physicians and midwives during pregnancy. More epidemiology data would be useful. IATROGENIC RISKS: Drug toxicity, generally related to the advancement of somatic development of the embryo and fetus, can appear at variable stages during pregnancy. Moreover, the pharmacokinetic properties of drugs are different during pregnancy. These facts must be taken into account when assessing the risk of uncontrolled drug use by pregnant women. RECOMMENDATIONS FOR PREGNANT WOMEN: Obstetricians, midwives and primary care physicians caring for pregnant women should explain the risks of self-medication. The specific features of disease during pregnancy should be considered when giving relevant information.

In vivo studies of the gamma subunit of retinal cGMP-phophodiesterase with a substitution of tyrosine-84.

The inhibitory rod cGMP phosphodiesterase gamma subunit (PDEgamma) is a major component of the photoresponse and is required to support rod integrity. Pdeg(tm1)/Pdeg(tm1) mice (which lack PDEgamma owing to a targeted disruption of the Pdeg gene) suffer from a very rapid and severe photoreceptor degeneration. The Y84G (Tyr(84)-->Gly) allele of PDEgamma has previously been shown in experiments carried out in vitro to reduce the regulatory control of the PDE catalytic core (PDEalphabeta) exerted by the wild-type gamma subunit. To determine the effects of this mutation on in vivo function, the murine opsin promoter was used to direct expression to the photoreceptors of +/Pdeg(tm1) mice of a mutant Y84G and a wild-type PDEgamma control transgene. The transgenic mice were crossed with Pdeg(tm1)/Pdeg(tm1) mice to generate animals able to synthesize only the transgenic PDEgamma. Our results showed that wild-type PDEgamma and Y84G transgenes could complement the Pdeg(tm1)/Pdeg(tm1) mutant for photoreceptor survival. The mutation caused a significant biochemical defect in PDE activation by transducin. However, the Y84G mutation did not fully eliminate the control of PDEgamma on the PDE catalytic core in vivo; the expression of the mutant subunit was associated with only a 10-fold reduction in the amplitude of the a-wave and a 1.5-fold decrease in the b-wave of the corneal electroretinogram. Unexpectedly, the mutation caused a much 'milder' phenotype in vivo than was predicted from the biochemical assays in vitro.

[Pharmacokinetics of beta blockers in hyperthyroidism. Therapeutic relevance]. / Pharmacocinétique des bêta-bloquants chez le sujet hyperthyroïdien. Intérêt thérapeutique.

Hyperthyroidism is associated with alterations in pharmacokinetic parameters such as absorption, distribution, metabolism and elimination. Beta-blockers are used in particular in the treatment of hyperthyroidism and are also subject to pharmacokinetic changes occurring during this pathology. The magnitude of these variations is examined when beta-blockers are used for clinical manifestations of hyperthyroidism or during thyroid surgery. Clinical means used to assess the accuracy of therapeutic drug monitoring are also described.

[Relationships between selenium deficiency and 3,5,3'-triiodothyronine (T3) synthesis]. / Relations entre le déficit en sélénium et la synthèse de 3,5,3'-triiodothyronine (T3).

Several enzymes, the main being type I 5' deiodinase, ensure thyroxin (T4) into 3,5,3'-triiodothyronine (T3) deiodination, both in the thyroid and in peripheral tissues. One of the feature of this enzymatic reaction is its regulation. It depends in part on individual selenium and iodine status. It has been shown by an analysis of thyroid hormones concentrations variations, when one of these trace elements is missing. During thyroid hormone synthesis, selenium and iodine are also implied in oxidative process control. Then, how selenium and iodine status balance modifications contribute to thyroidal diseases outbreak, becomes easier to understand. Besides, providing, adapted to individual requirements, selenium and iodine supplies could be useful for hypothyroidism and hyperthyroidism treatment.