Number of lymph nodes sampled in SFCE/SIOP 2001 patients with Wilms tumour: Is the goal of more than six achievable?

AIM: The number of lymph nodes (LN) that should be sampled during nephrectomy for Wilms tumour (WT) remains controversial but of utmost importance for staging purposes. The aim of this French national retrospective study of patients enrolled in SIOPWT2001 trial was to analyse the number of LN sampled according to their site and to determine if the number of six asked by the International Society of Paediatric Oncology - Renal Tumour Study Group (SIOP-RTSG) UMBRELLA protocol is achievable. METHODS: We reviewed the data collected on central pathology review forms from 2002 to 2014 for only unilateral WT. LN were divided whether they were clearly identified by surgeons at nephrectomy or only found by pathologists on the nephrectomy specimen. RESULTS: A total of 539 patients (240 male/299 female) were included (458 localized/81 metastatic). Median age at surgery was 41.3 months [0-189]. The number of LN sampled was 0, 1-6, ≥7 and unknown in 69 (12.8%), 293 (54.3%), 160 (29.7%) and 17 (3.2%) cases, respectively. The number of patients with sampled LN were higher if LN were identified by both the pathologist and the surgeon (n = 231, 42.8%) (p = < .001). At least one invaded LN (LN+) was found in 66 patients (12.2%), more than half being found among patients having LN sampled by both pathologist and surgeon (p < .001). The mean number of identified LN was six if no LN+ was detected on final histological analysis, while it was 11 in case of LN+ (p < .001). CONCLUSIONS: The aim of sampling more than six LN is achievable, but only with the active collaboration of both surgeons and pathologists.

Standard of care for adult Wilms tumor? From adult urologist to pediatric oncologist. A retrospective review.

Nephroblastoma or Wilms tumor, a common embryonal tumor in children, can occasionally occur in adults. The survival of patients older than 18 years is reported to be significantly inferior to that of pediatric patients. Establishing a diagnosis for these rare tumors can be challenging for both clinicians and pathologists, who are not accustomed to considering Wilms tumor as a potential differential in adults. This leads to misdiagnosis and a subsequent delay in the initiation of appropriate therapy. The standard of care is not well established for Wilms tumors in adults. We provide here a comprehensive review of the international literature on the subject with the current management protocols in France. We also propose the need of strong inter-disciplinary collaboration between surgeons, pathologists, and medical and pediatric oncologists for increasing knowledge and formulating treatment strategies for these rare tumors. Homogenous guidelines for treating adults with Wilms tumors have been proposed for all patients in France.

Evaluation of the nephron-sparing surgery formula in Wilms tumors.

AIM: Definitions of nephron-sparing surgery (NSS) procedures in Wilms tumor (WT) are not clear. The new UMBRELLA protocol offers a formula (NSS(X)-SRM(n)-PRM(n)-RRP(n%)) to better define the different NSS parameters. We aimed to assess the advantages and limits of this new formula. METHODS: This retrospective monocentric study included patients operated by NSS for WT from 1975 to 2018. We reviewed the medical records and applied the NSS formula to all included patients. RESULTS: Eighty kidneys were operated on 56 patients at a mean age of 19.2 months (4 days-7.5 years), with 49 partial nephrectomies and 31 tumorectomies. The assessment of the surgical resection margins (SRM) showed a doubt in six cases and one tumor breach. An intact pseudocapsule along the resection margin with no renal parenchyma was found in four cases at pathological resection margins (PRM) assessment, whereas a tumor breach was described in seven cases. Among the six patients with a surgical doubt, only one had a pathological stage III. There were no surgical doubts in the seven patients with tumor breach at pathology. At a mean follow-up of eight years (15 days-28.6 years), eight patients had elevated blood pressure levels. Ten had proteinuria. These two parameters were significantly increased in patients with a remaining renal parenchyma (RRP) of less than half of the initial total renal parenchyma. The serum creatinine level was normal for all except two patients. CONCLUSION: The new NSS formula described all the crucial elements of NSS. RRP seemed essential for the evaluation of long-term renal function.

PTPN11 mutations in canine and human disseminated histiocytic sarcoma.

In humans, histiocytic sarcoma (HS) is an aggressive cancer involving histiocytes. Its rarity and heterogeneity explain that treatment remains a challenge. Sharing high clinical and histopathological similarities with human HS, the canine HS is conversely frequent in specific breeds and thus constitutes a unique spontaneous model for human HS to decipher the genetic bases and to explore therapeutic options. We identified sequence alterations in the MAPK pathway in at least 63.9% (71/111) of HS cases with mutually exclusive BRAF (0.9%; 1/111), KRAS (7.2%; 8/111) and PTPN11 (56.75%; 63/111) mutations concentrated at hotspots common to human cancers. Recurrent PTPN11 mutations are associated to visceral disseminated HS subtype in dogs, the most aggressive clinical presentation. We then identified PTPN11 mutations in 3/19 (15.7%) human HS patients. Thus, we propose PTPN11 mutations as key events for a specific subset of human and canine HS: the visceral disseminated form. Finally, by testing drugs targeting the MAPK pathway in eight canine HS cell lines, we identified a better anti-proliferation activity of MEK inhibitors than PTPN11 inhibitors in canine HS neoplastic cells. In combination, these results illustrate the relevance of naturally affected dogs in deciphering genetic mechanisms and selecting efficient targeted therapies for such rare and aggressive cancers in humans.

Childhood pulmonary Langerhans cell histiocytosis: a comprehensive clinical-histopathological and BRAFV600E mutation study from the French national cohort.

Childhood pulmonary Langerhans cell histiocytosis (PLCH) is a rare disease. Its pulmonary histopathology, according to comprehensive clinical-radiological findings and BRAFV600E mutation status, has not yet been thoroughly documented. From the 167 childhood PLCH cases entered in the French National Histiocytosis Registry (1983-2016), we retrieved lung biopsies from a consecutive retrospective series of 17 patients, diagnosed when they were 2 weeks to 16 years old (median, 9.4 years), and report the clinical and histopathological findings herein. Histological analyses of biopsies (16 surgical and 1 postmortem) found the following features, alone or associated: Langerhans cell (LC) nodules with cavitation (9/17), cysts (14/17), fibrotic scars (2/17), peribronchiolar topographic distribution of the lesions (10/17), and accessory changes, like stretch emphysema (7/17). Those characteristics closely resemble those describing adult PLCH. However, unusual findings observed were 2 large nodules and a diffuse interstitial LC infiltrate. BRAFV600E mutation was detected in 4 of 12 samples tested, notably in the 3 with unusual features. In conclusion, childhood PLCH mostly shares the common histology features already described in adult PLCH, regardless of age. Because smoking is considered the major trigger in PLCH pathogenesis, the findings based on this series suggest other inducers of bronchiolar LC recruitment, especially in very young patients.

[Nodular lymphocyte-predominant Hodgkin lymphoma in children: clinical course, biology, and management]. / Lymphome de Hodgkin nodulaire à prédominance lymphocytaire chez l'enfant : présentation clinique, biologique et prise en charge actuelle.

Nodular lymphocyte predominant Hodgkin disease (NLPHL) differs clearly from classical Hodgkin lymphoma (cHL) by clinical presentation and more favorable outcome. Patients often present with early stage IA or IIA. Extranodal disease and B-symptoms are uncommon. Histologically, NLPHL is characterized by the presence of atypical "lymphocyte predominant cells" (LP cells) or "pop-corn" cells in a non-neoplastic and reactionnal nodular background of small mature B-lymphocytes. LP cells are negative for CD30 and positive for CD20, BCL6 and EMA (in half of the cases). FDG-PET plays an important role in evaluation of cHL and NLPHL for staging, therapy assessment and relapse. Historically, patients with NLPHL have been treated like patients with cHL, but their very favorable prognosis and the risk of late complications of chemotherapy and/or radiotherapy have led to a de-escalation in recent years. Patients with early stage could be treated by surgical adenectomy alone or associated with not intensive chemotherapy. Currently, there is no consensus regarding to the optimal treatment of patients with advanced stage. Rituximab used as monotherapy or in association with chemotherapy has achieved complete or partial responses. The outcome of NLPHL is singular by the frequent occurrence of late relapses and the risk of transformation into aggressive B lymphoma justifying an extended follow-up. Further prospective studies are needed to optimize treatment of these advanced and recurrent forms.

Efficient hepatocyte engraftment in a nonhuman primate model after partial portal vein embolization.

BACKGROUND: Hepatocyte transplantation could be an alternative to whole liver transplantation for the treatment of metabolic liver diseases. However, the results of clinical investigations suggest that the number of engrafted hepatocytes was insufficient to correct metabolic disorders. This may partly result from a lack of proliferation of transplanted hepatocytes. In rodents, portal ligation enhances hepatocyte engraftment after transplantation. We investigated the effects of partial portal ligation and embolization on engraftment and proliferation of transplanted hepatocytes in primates. METHODS: Hepatocyte autotransplantation was performed in Macaca monkeys. The left lateral lobe was resected for hepatocyte isolation. The first group of monkeys underwent surgical ligation of the left and right anterior portal branches; in the second group, the same portal territories were obstructed by embolization with biological glue. To evaluate the proportion of cell engraftment hepatocytes were Hoechst-labeled and transplanted via the portal vein. Cell proliferation was measured by BrdU incorporation. RESULTS: Hepatocyte proliferation was induced by both procedures but it was significantly higher after partial portal embolization (23.5% and 11.2% of dividing hepatocytes on days 3 and 7) than after ligation (3% and 0.8%). Hepatocytes engrafted more efficiently after embolization than after ligation. They proliferated and participated to liver regeneration representing 10% of the liver mass on day seven and their number remained constant on day 15. CONCLUSIONS: These data suggest that partial portal embolization of the recipient liver improves engraftment of transplanted hepatocytes in a primate preclinical model providing a new strategy for hepatocyte transplantation.

Chemokine RANTES in severe pulmonary arterial hypertension.

The recent discovery that sporadic and familial primary pulmonary hypertension can be associated with germline mutations of genes encoding receptor members of the transforming growth factor-beta family has focused much attention on cytokines and growth factors in pulmonary vascular disorders. Production of several cytokines has been demonstrated in severe pulmonary arterial hypertension, emphasizing the possible influence of inflammatory mechanisms in this condition. Moreover, perivascular inflammatory cell infiltrates composed of macrophages and lymphocytes have been detected in plexiform lesions of primary pulmonary hypertension. Chemokine RANTES is an important chemoattractant for monocytes and T cells. We therefore hypothesize that chemokine RANTES promotes cell recruitment in the lungs of patients displaying severe pulmonary arterial hypertension. Reverse transcriptase polymerase chain reaction demonstrated elevated RANTES mRNA expression in 10 lung samples from patients with severe pulmonary arterial hypertension, as compared with seven control subjects. In situ hybridization and immunohistochemistry confirmed that endothelial cells were the major source of RANTES within the pulmonary artery wall of the patients. Serial sections analysis showed that RANTES expression was associated with CD45+ inflammatory cell infiltrates. These results support the concept that inflammatory mechanisms play a role in the natural history of pulmonary arterial hypertension.