PROM2 overexpression induces metastatic potential through epithelial-to-mesenchymal transition and ferroptosis resistance in human cancers.

INTRODUCTION: Despite considerable therapeutic advances in the last 20 years, metastatic cancers remain a major cause of death. We previously identified prominin-2 (PROM2) as a biomarker predictive of distant metastases and decreased survival, thus providing a promising bio-target. In this translational study, we set out to decipher the biological roles of PROM2 during the metastatic process and resistance to cell death, in particular for metastatic melanoma. METHODS AND RESULTS: Methods and results: We demonstrated that PROM2 overexpression was closely linked to an increased metastatic potential through the increase of epithelial-to-mesenchymal transition (EMT) marker expression and ferroptosis resistance. This was also found in renal cell carcinoma and triple negative breast cancer patient-derived xenograft models. Using an oligonucleotide anti-sense anti-PROM2, we efficaciously decreased PROM2 expression and prevented metastases in melanoma xenografts. We also demonstrated that PROM2 was implicated in an aggravation loop, contributing to increase the metastatic burden both in murine metastatic models and in patients with metastatic melanoma. The metastatic burden is closely linked to PROM2 expression through the expression of EMT markers and ferroptosis cell death resistance in a deterioration loop. CONCLUSION: Our results open the way for further studies using PROM2 as a bio-target in resort situations in human metastatic melanoma and also in other cancer types.

Metastatic clear-cell renal cell carcinoma: a frequent NOTCH1 mutation predictive of response to anti-NOTCH1 CB-103 treatment.

BACKGROUND: Clear-cell renal cell carcinomas (ccRCCs) are malignant tumors with high metastatic potential and resistance to treatments occurs almost constantly. Compared to primary tumors, there are still limited genomic data that has been obtained from metastatic samples. METHODS: We aimed to characterize metastatic ccRCC by way of whole-genome analyses of metastatic formalin-fixed samples, using OncoScan® technology. We identified a frequent, unexpected pL1575P NOTCH1 mutation which we set out to characterize for translational purposes. We thus implemented patient-derived xenografts from metastatic samples of human ccRCC to explore its clinical significance. RESULTS: We showed that pL1575P NOTCH1 mutation was an activating mutation, leading to the expression of NOTCH1-intracellular domain-active fragments in both cancer cells and tumor endothelial cells, suggesting a trans-differentiation of cancer cells into tumor micro-vessels. We demonstrated that this mutation could be used as a predictive biomarker of response to CB-103, a specific NOTCH1-intracellular domain inhibitor. One striking result was the considerable anti-angiogenic effect, coherent with the presence of NOTCH1 mutation in tumor micro-vessels. CONCLUSIONS: We identified a frequent, unexpected pL1575P_c4724T_C NOTCH1 mutation as a new biomarker for ccRCC metastases, predictive of response to the CB103 NOTCH1-intracellular domain inhibitor.

Severe post-renal acute kidney injury, post-obstructive diuresis and renal recovery.

UNLABELLED: Study Type--Therapy (case series) Level of Evidence 4. What's known on the subject? and What does the study add? The pathophysiology of post-renal acute kidney injury (PR-AKI), i.e. caused by urinary tract obstruction, has been extensively studied in animal models but clinical studies on this subject are outdated, and/or have focused on the mechanisms of 'post-obstructive diuresis' (POD), a potentially life-threatening polyuria that can develop after the release of obstruction. In severe PR-AKI, the risk of occurrence of POD is high. POD occurrence predicts renal recovery without the persistence of severe chronic kidney failure. In the present study, the occurrence of POD and the persistence of chronic renal sequelae could be predicted early from clinical variables at admission before the release of obstruction. OBJECTIVE: • To identify predictors of post-obstructive diuresis (POD) occurrence or severe chronic renal failure (CRF) persistence after the release of urinary tract obstruction in the setting of post-renal acute kidney injury (PR-AKI). PATIENTS AND METHODS: • Bi-centre retrospective observational study of all patients with PR-AKI treated in two intensive care units (ICUs) from 1998 to 2010. • Clinical, biological and imaging characteristics on admission and after the release of obstruction were analysed with univariate and, if possible, multivariate analysis to search for predictors of (i) occurrence of POD (diuresis >4 L/day) after the release of obstruction; (ii) persistence of severe CRF (estimated glomerular filtration rate <30 mL/min/1.73 m(2), including end-stage CRF) at 3 months. RESULTS: • On admission, median (range) serum creatinine was 866 (247-3119) µmol/L. • POD occurred in 34 (63%) of the 54 analysable patients. On admission, higher serum creatinine (Odds ratio [OR] 1.002 per 1 µmol/L, 95% confidence interval [CI] 1.000-1.004, P = 0.004), higher serum bicarbonate (OR 1.36 per 1 mmol/L, 95% CI 1.13-1.65, P < 0.001), and urinary retention (OR 6.96, 95% CI 1.34-36.23, P = 0.01) independently predicted POD occurrence. • Severe CRF persisted in seven (21%) of the 34 analysable patients, including two (6%) cases of end-stage CRF. Predictors of severe CRF persistence after univariate analysis were: lower blood haemoglobin (P < 0.001) and lower serum bicarbonate (P = 0.03) on admission, longer time from admission to the release of obstruction (P = 0.01) and absence of POD (P = 0.04) after the release of obstruction. CONCLUSIONS: • In severe PR-AKI treated in ICU, POD occurrence was a frequent event that predicted renal recovery without severe CRF. • POD occurrence or severe CRF persistence could be predicted early from clinical and biological variables at admission before the release of obstruction.

Novel FH mutations in families with hereditary leiomyomatosis and renal cell cancer (HLRCC) and patients with isolated type 2 papillary renal cell carcinoma.

BACKGROUND: Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant disorder predisposing humans to cutaneous and uterine leiomyomas; in 20% of affected families, type 2 papillary renal cell cancers (PRCCII) also occur with aggressive course and poor prognosis. HLRCC results from heterozygous germline mutations in the tumour suppressor fumarate hydratase (FH) gene. METHODS: As part of the French National Cancer Institute (INCa) 'Inherited predispositions to kidney cancer' network, sequence analysis and a functional study of FH were preformed in 56 families with clinically proven or suspected HLRCC and in 23 patients with isolated PRCCII (5 familial and 18 sporadic). RESULTS: The study identified 32 different germline FH mutations (15 missense, 6 frameshifts, 4 nonsense, 1 deletion/insertion, 5 splice site, and 1 complete deletion) in 40/56 (71.4%) families with proven or suspected HLRCC and in 4/23 (17.4%) probands with PRCCII alone, including 2 sporadic cases. 21 of these were novel and all were demonstrated as deleterious by significant reduction of FH enzymatic activity. In addition, 5 asymptomatic parents in 3 families were confirmed as carrying disease-causing mutations. CONCLUSIONS: This study identified and characterised 21 novel FH mutations and demonstrated that PRCCII can be the only one manifestation of HLRCC. Due to the incomplete penetrance of HLRCC, the authors propose to extend the FH mutation analysis to every patient with PRCCII occurring before 40 years of age or when renal tumour harbours characteristic histologic features, in order to discover previously ignored HLRCC affected families.

[Bladder cancer in neurological patients: analysis of a single-centre series]. / Cancers de la vessie chez les patients neurologiques: analyse d'une série monocentrique.

OBJECTIVE: To report the prevalence, aetiologies and course of bladder cancer in our population of neurological patients. MATERIALS AND METHODS: The case files of 1825 neurological patients followed in our department between 2000 and 2006 were retrospectively reviewed. The following data were recorded in patients with bladder tumour: age, gender smoking, aetiology of the neurological disease, voiding mode, history of neurogenic bladder, mode of discovery, histological type, grade, TNM stage, treatment and outcome. RESULTS: Eight neurological patients (0.44%) developed bladder cancer. The mean age was 58.8 13.7 years (range: 36-72 years). The male/female sex ratio was 3. Neurogenic bladder was due to: spinal cord injury (n=4), multiple sclerosis (n=1), spina bifida (n=1), familial spastic paraplegia (n=1) and idiopathic peripheral syndrome (n=1). Three cases of squamous cell carcinoma (37.5%) were diagnosed. Seven tumours were high grade and 7 were invasive (> or = pT2) The mean follow-up was 27.8 +/- 23.5 months (range: 14-71 months). Three patients have died. CONCLUSION: The incidence of bladder cancer in neurological patients is similar to that of the general population. However, more immediately invasive squamous cell carcinomas are observed, requiring aggressive treatment, but no consensus concerning a surveillance protocol adapted to this population has been published.

[Surgical learning curve for creation of vascular accesses for haemodialysis: value of medico-radio-surgical collaboration]. / Apprentissage chirurgical de la création des abords vasculaires pour hémodialyse: intérêt de la collaboration médico-radio-chirurgicale.

INTRODUCTION: Creation of a vascular access (VA) for haemodialysis is a surgical procedure which comprises a failure rate related to the quality of the vessels and the operator's experience. The authors report the first 2 years of a young urologist's experience with this procedure in a local hospital in collaboration with the nephrology team. PATIENTS AND METHODS: Patients undergoing creation of VA were divided into 2 chronological groups. The patient's age and gender, the cause of renal failure, the presence of diabetes, clinical examination of the upper limb, preoperative assessment of upper limb vessels, the type of anaesthesia, the operating time and the start of dialysis after the operation, as well as the functional results of the VA at 6 months were studied. Results concerning the patients of the first period were discussed by the operator and the nephrology team. RESULTS: During the first 9 months, 28 patients were operated, corresponding to 36 operations including 32 direct fistulas. Over the following 15 months, 61 patients were operated, with the creation of 63 VAs, including 55 direct fistulas. The failure rate (thrombosis or non-functioning VA) decreased from 32.1% to 11.1% (p=0.07), while the 2 groups were globally comparable. CONCLUSION: Evaluation of a new surgical procedure shows a number of failures, as for all learning curves. However, it helps to improve the results. Collaboration with nephrologists must comprise a discussion allowing the acceptance of certain failures, as they reflect compliance with a strategy of preservation of the vascular capital and a rational attempt to avoid a non-essential proximal access or bypass graft. The support of a motivated radiology team (preoperative assessment and management of complications) and the assistance of a more experienced operator are essential.

[Medical management of post-obstruction diuresis syndromes]. / Prise en charge médicale des syndromes de levée d'obstacle.

The presence of urinary tract obstruction affects the proximal urinary tract by altering renal filtration and excretion functions, resulting in accumulation of electrolytes. Many pathophysiological mechanisms are also involved during obstruction and may be expressed secondarily. For example, relief of obstruction, which restores free flow of urine, is accompanied by marked diuresis and electrolyte disorders. The post-obstruction diuresis syndrome can lead to dehydration, or even shock and acute renal failure. Strict and specialized monitoring is required during the post-obstruction phase. Medical management is designed to avoid serious haemodynamic and metabolic disorders.

[Emphysematous cystitis complicating non-conservative total hysterectomy for ovarian cancer]. / Cystite emphysémateuse compliquant une hystérectomie totale non conservatrice pour cancer de l'ovaire.

The authors report a case of emphysematous cystitis in a 50-year-old woman treated by corticosteroids, occurring 1 month after hysterectomy for locally advanced ovarian cancer. Although the patient presented a vesico-vaginal fistula, the presence of air in the bladder wall and only in the bladder lumen, confirmed the diagnosis of emphysematous cystitis. Despite intensive care and surgery with colostomy and Mikulicz drainage associated with urinary diversion (transparietal bladder catheter on one side and cutaneous ureterostomy on the other side), the patient died on day 10 in a context of sepsis. The circumstances of discovery, the various clinical forms and the radiological features of emphysematous cystitis described in the literature are reviewed together with the modalities of management.

No evidence for a genetic modifier for renal cell cancer risk in HLRCC syndrome.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a tumor predisposition syndrome caused by heterozygous germline mutations in the fumarate hydratase (FH) gene. Cutaneous and uterine leiomyomas are the most common clinical manifestations of HLRCC, whereas only approximately 20% of the families display renal cell cancer (RCC). The number of RCC cases in these families varies from one to five. Interestingly, families with multiple RCC cases are mainly found in Finland and the USA. Such aggregation of RCC in only some families and populations has led to the hypothesis that besides FH mutations also other inherited genetic and/or environmental factors may contribute to the malignant kidney tumor formation. To search for such a genetic modifier we have performed a genome-wide linkage analysis in two and an identical by descent analysis in four Finnish HLRCC families with several RCC patients. Additional Finnish and French families were used in fine-mapping and haplotype analyses. The only region compatible with linkage was the locus surrounding the FH gene itself in chromosome 1q43. The genes in the putative candidate region were screened, but no potentially pathogenic alterations were observed. Although these data do not rule out the existence of a genetic modifier, they emphasize the contribution of the FH genotype in HLRCC related RCC. Therefore, as all FH mutation carriers may have an increased risk for developing renal cancer, counseling and genetic testing should be offered for all HLRCC family members and clinical follow-up should be organized for the mutation carriers.