Long-term outcome for children undergoing open hepatico-jejunostomy for choledochal malformations: a 43-year single-center experience.

PURPOSE: To report on our 43-year single-center experience with children operated on for Choledochal Malformations (CMs), focusing on long-term results and Quality of life (QoL). MATERIALS AND METHODS: All consecutive pediatric patients with CMs who underwent surgical treatment at our center between October 1980 and December 2022 were enrolled in this retrospective study. We focused on long-term postoperative complications (POCs), considered to be complications arising at least 5 years after surgery. We analyzed QoL status once patients reached adulthood, comparing the results with a control group of the same age and sex. RESULTS: One hundred and thirteen patients underwent open excision of CMs with a Roux-en-Y hepaticojejunostomy (HJ). The median follow-up was 8.95 years (IQR: 3.74-24.41). Major long-term POCs occurred in six patients (8.9%), with a median presentation of 11 years after surgery. The oldest patient is currently 51. No cases of biliary malignancy were detected. The QoL of our patients was comparable with the control group. CONCLUSION: Our experience suggests that open complete excision of CMs with HJ achieves excellent results in terms of long-term postoperative outcomes. However, since the most severe complications can occur many years after surgery, international cooperation is advisable to define a precise transitional care follow-up protocol.

Florida-California Cancer Health Equity Center (CaRE2) Community Scientist Research Advocacy Program.

The Community Scientist Program (CSP), a model connecting researchers with community members, is effective to inform and involve the general population in health-related clinical research. Given the existing cancer disparities among Black/African American and Hispanic/Latino/a populations, more models describing how cancer-related CSPs are designed, implemented, and evaluated are needed. The Florida-California Cancer Research, Education and Engagement (CaRE2) Health Equity Center is a tri-institutional, bicoastal center created to eliminate cancer health disparities among Black/African American and Hispanic/Latino/a populations living in California and in Florida. The CaRE2 Center created a Community Scientist Research Advocacy (CSRA) training program for community members to become cancer research advocates. The CSRA program is currently a 13-week program conducted 100% virtually with all materials provided in English and Spanish for participants to learn more about prostate, lung, and pancreas cancers, ongoing research at CaRE2, and ways to share cancer research throughout their communities. Participants attend didactic lectures on cancer research during weeks 1-5. In week 4, participants join CSRA self-selected groups based on cancer-related topics of interest. Each group presents their cancer-related advocacy project developed during weeks 5-12 at the final session. In this paper, we describe the CaRE2 Health Equity Center's CSRA program, share results, and discuss opportunities for improvement in future program evaluation as well as replication of this model in other communities.

Microvascular tissue perfusion after postcatheterization pseudoaneurysm treatment.

BACKGROUND: Femoral pseudoaneurysm (PSA) is a severe complication after endovascular procedures. Ultrasound-guided manual compression (MC) and percutaneous thrombin injection (TI) are frequently used treatments. MC is less effective, TI may cause thromboembolic events. OBJECTIVE: Up to date, there is no data regarding impairment of microvascular tissue perfusion after PSA treatment. METHODS: In this single-center, prospective study 22 patients with PSA were included. We compared macro- and microcirculatory perfusion in the treated and untreated leg at baseline before, after and one day after treatment. Leg perfusion was assessed with ultrasound and ankle-brachial index (ABI). Microcirculatory perfusion of the feet was measured with a near-infrared spectroscopy (NIRS) camera generating StO2-tissue-maps. RESULTS: Successful PSA thrombosis was achieved in 16 (100%) patients in TI group and in 4 (66.7%) patients in MC group. There was no evidence of arterial thrombi on ultrasound and the ABI did not differ between groups. NIRS StO2-tissue-maps of the feet showed no significant difference in both groups concerning the treated (p = 0.121) or the untreated (p = 0.198) leg during follow up. CONCLUSIONS: In this small exploratory study, there was no evidence of micro- and macrovascular tissue perfusion impairment after treatment of postcatheterization femoral pseudoaneurysm with thrombin injection underscoring the safety of this approach.

[Evolution and progress of lung transplantation: An analysis of a cohort of 600 lung transplant patients at the Hospital Foch]. / Évolution et progrès en transplantation pulmonaire : étude de la cohorte de 600 premiers patients transplantés pulmonaires à l'hôpital Foch.

Lung transplantation is deemed to be the only effective therapy that improves survival for patients with end stage lung disease. The aim of our study was to examine the progress achieved over the last two decades and to demonstrate the effectiveness and safety of this treatment. METHODS: A retrospective analysis of a cohort of 600 consecutive lung transplant patients treated at the hospital Foch (Suresnes, France) between 1988 and 2014. They were split into three groups of 200 patients each: 1988-2004, 2004-2011, 2011-2014. RESULTS: Time and mortality on waiting list, perioperative mortality, the incidence of acute rejection in the first year and chronic lung allograft dysfunction (CLAD) at 5 years posttransplantation, have all decreased. Global survival at 1 and 5 years for the 600 patients increased from 78% and 57% to 86% and 75% respectively for the 200 last patients. Patients with cystic fibrosis have a better 5 year survival than those with emphysema or pulmonary fibrosis (68% vs. 54 % for emphysema and 37% for fibrosis). For the last 200 patients, 5 year survival is 81% for CF patients, 78 % for emphysema and 47% for fibrosis. Emergency transplantation had a 60% 5 years survival. Proliferative complications, arterial hypertension and renal function impairment are being monitored long term. CONCLUSION: The twenty-five years experience shows a consistent improvement in the results of lung transplantation which is now accepted as the only effective curative treatment for end stage lung disease.

Starting the fight in the tumor: expert recommendations for the development of human intratumoral immunotherapy (HIT-IT).

A European Society for Medical Oncology (ESMO)-sponsored expert meeting was held in Paris on 8 March 2018 which comprised 11 experts from academia, 11 experts from the pharmaceutical industry and 2 clinicians who were representatives of ESMO. The focus of the meeting was exclusively on the intratumoral injection/delivery of immunostimulatory agents with the aim of harmonizing the standard terms and methodologies used in the reporting of human intratumoral immunotherapy (HIT-IT) clinical trials to ensure quality assurance and avoid a blurring of the data reported from different studies. The goal was to provide a reference document, endorsed by the panel members that could provide guidance to clinical investigators, pharmaceutical companies, ethics committees, independent review boards, patient advocates and the regulatory authorities and promote an increase in the number and quality of HIT-IT clinical trials in the future. Particular emphasis was placed not only on the development of precise definitions to facilitate a better understanding between investigators but also on the importance of systematic serial biopsies as a driver for translational research and the need for the recording and reporting of data, to facilitate a better understanding of the key processes involved.

Actionable perturbations of damage responses by TCL1/ATM and epigenetic lesions form the basis of T-PLL.

T-cell prolymphocytic leukemia (T-PLL) is a rare and poor-prognostic mature T-cell malignancy. Here we integrated large-scale profiling data of alterations in gene expression, allelic copy number (CN), and nucleotide sequences in 111 well-characterized patients. Besides prominent signatures of T-cell activation and prevalent clonal variants, we also identify novel hot-spots for CN variability, fusion molecules, alternative transcripts, and progression-associated dynamics. The overall lesional spectrum of T-PLL is mainly annotated to axes of DNA damage responses, T-cell receptor/cytokine signaling, and histone modulation. We formulate a multi-dimensional model of T-PLL pathogenesis centered around a unique combination of TCL1 overexpression with damaging ATM aberrations as initiating core lesions. The effects imposed by TCL1 cooperate with compromised ATM toward a leukemogenic phenotype of impaired DNA damage processing. Dysfunctional ATM appears inefficient in alleviating elevated redox burdens and telomere attrition and in evoking a p53-dependent apoptotic response to genotoxic insults. As non-genotoxic strategies, synergistic combinations of p53 reactivators and deacetylase inhibitors reinstate such cell death execution.

Discovery of novel drug sensitivities in T-PLL by high-throughput ex vivo drug testing and mutation profiling.

T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive neoplasm of mature T-cells with an urgent need for rationally designed therapies to address its notoriously chemo-refractory behavior. The median survival of T-PLL patients is <2 years and clinical trials are difficult to execute. Here we systematically explored the diversity of drug responses in T-PLL patient samples using an ex vivo drug sensitivity and resistance testing platform and correlated the findings with somatic mutations and gene expression profiles. Intriguingly, all T-PLL samples were sensitive to the cyclin-dependent kinase inhibitor SNS-032, which overcame stromal-cell-mediated protection and elicited robust p53-activation and apoptosis. Across all patients, the most effective classes of compounds were histone deacetylase, phosphoinositide-3 kinase/AKT/mammalian target of rapamycin, heat-shock protein 90 and BH3-family protein inhibitors as well as p53 activators, indicating previously unexplored, novel targeted approaches for treating T-PLL. Although Janus-activated kinase-signal transducer and activator of transcription factor (JAK-STAT) pathway mutations were common in T-PLL (71% of patients), JAK-STAT inhibitor responses were not directly linked to those or other T-PLL-specific lesions. Overall, we found that genetic markers do not readily translate into novel effective therapeutic vulnerabilities. In conclusion, novel classes of compounds with high efficacy in T-PLL were discovered with the comprehensive ex vivo drug screening platform warranting further studies of synergisms and clinical testing.

Breast and ovarian cancer predisposition due to de novo BRCA1 and BRCA2 mutations.

BRCA1 and BRCA2 are the two major genes predisposing to breast and ovarian cancer. Whereas high de novo mutation rates have been demonstrated for several genes, only 11 cases of de novo BRCA1/2 mutations have been reported to date and the BRCA1/2 de novo mutation rate remains unknown. The present study was designed to fill this gap based on a series of 12 805 consecutive unrelated patients diagnosed with breast and/or ovarian cancer who met the inclusion criteria for BRCA1/2 gene analysis according to French guidelines. BRCA1/2 mutations were detected in 1527 (12%) patients, and three BRCA1 mutations and one BRCA2 mutation were de novo. The BRCA1/2 de novo mutation rate was estimated to be 0.3% (0.1%; 0.7%). Although rare, it may be useful to take the possibility of de novo BRCA1/2 mutation into account in genetic counseling of relatives and to improve the understanding of complex family histories of breast and ovarian cancers.

Autologous hematopoietic stem cell transplantation reverses skin fibrosis but does not change skin vessel density in patients with systemic sclerosis.

Hematopoetic stem cell transplantation (HSCT) improves survival in patients with severe systemic sclerosis (SSc) by resetting the immune system. We studied how HSCT acts on the key SSc skin pathology findings (fibrosis and vascularization). In mean, 3 skin punch biopsies per patient (range 2-6) were analyzed from 13 patients (5 females) with severe diffuse SSc before and up to 96 months after HSCT. Fibrosis of the four skin layers was graded semi-quantitatively and an overall fibrosis score was then calculated. Vessel numbers and calibers were assessed in the superficial and deeper dermis after immune-staining for endothelial antigens (CD31, VE-cadherin and vWF). The median age of patients at HSCT was 47 (24-64) years. The overall median modified Rodnan skin score decreased from 24 to 10 (P=0.003) at first follow-up within a median of 9 (6-36) months after HSCT as did the histological skin score (P=0.03). The modified Rodnan skin score and the fibrosis score correlated positively (r=0.589, P<0.001). The vessels density did not significantly change after HSCT nor did the expression of the tested endothelial markers. Although improving skin fibrosis in patients with SSc, HSCT does not alter vessel density within skin biopsies.

Genetic landscape of uveal melanoma.

Uveal melanoma is genetically one of the simplest malignant tumors in adults. Initiation of these tumors is dependent of an oncogenic mutation in the GNAQ or GNA11 genes present in almost all cases. The nature of second mutational events is of major interest as it monosomy 3, gain of 8q and BAP1 inactivation are associated with unfavorable prognosis while SF3BI or EIF1AX are of good prognosis. Despite their common lineage, cutaneous and uveal melanomas are distinct diseases, implicating different oncogenic pathways and contrasting mutational landscapes. Even if uveal melanoma is a simple tumor, it is also one of the deadliest tumors in adults. There is a major clinical need for drugs targeting either the downstream pathways of Gαq and Gα11 or the biological cell functions dysregulated by BAP1 loss of function.

Inter-individual differences in HLA expression can impact the CDC crossmatch.

How human leucocyte antigen (HLA) expression levels on human lymphocytes relate to clinically relevant in vitro cytotoxicity testing has not been defined. Here, cross-sectional (n = 14) and longitudinal (n = 6) semi-quantitative assessment of HLA expression on lymphocytes was performed. Complement-dependent cytotoxicity (CDC) and cellular allo-reactivity were assessed vis-à-vis target cells with defined levels of HLA expression. On CD4(+) and CD8(+) T-cells, and on B-cells, intra-individual HLA levels varied ≤1.5-fold, whereas inter-individual HLA expression varied 2.34-fold and 2.07-fold on CD4(+) and CD8(+) T-cells, respectively, and 2.90-fold on B-cells. Importantly, CDC crossmatch reactions induced by anti-HLA-A2 monoclonal antibody as well as patient sera solely containing HLA-A2 antibodies were significantly impacted by HLA-A2 expression levels on donor cells. Likewise, cytotoxicity of HLA-A2 reactive effector cells was induced proportionate to availability of HLA-A2. These data demonstrate that human HLA expression on lymphocytes from healthy blood donors is fairly stable intra-individually, yet varies significantly from person to person. Variability in HLA expression levels can impact functional cytotoxic reactions in vitro, including the widely used CDC crossmatch assay. Prospective studies are required to test the clinical relevance of this finding.

[The management of lung transplantation candidates. A case series]. / Préparation des insuffisants respiratoires à la transplantation. Un état des lieux.

INTRODUCTION: Lung transplantation (LT) is associated with an increased risk of infection, cancer, chronic renal failure, cardiovascular disease and osteoporosis. Some risk factors precede transplantation and could benefit for early diagnosis and optimised care. METHODS: The incidence of comorbidities and their treatment before referral were assessed in 157 consecutive lung transplant candidates between 2008 and 2011. RESULTS: The median age was 37years [25; 51]. Fifty-six percent had a body mass index below 19kg/m(2). In the COPD group, only 50 % had undergone a pulmonary rehabilitation program in the preceding 2 years. Osteoporosis was present in 42 %, of whom 36 % were on bisphophonate therapy. Vitamin D deficiency was present in 65 %. Previously undiagnosed cardiovascular risk factors were discovered during LT assessment: hypertension in one patient, hypercholesterolemia in 6 % and diabetes in 4 %. Poor dental condition necessitating extractions were found in 41 % of patients. Protective anti-HBs antibodies levels were present in 50 % of the patients at the time of referral. CONCLUSION: The assessment and early treatment of nutritional disorders, osteoporosis and risk factors for infection as well as addressing associated cardiovascular risk factors should be optimised in the care of patients with chronic respiratory insufficiency. The potential for becoming a lung transplant candidate in the future should be kept in mind early in the global management of those patients.

Preparing for the future: An examination of healthcare provider and patient communication regarding childhood cancer survivorship.

BACKGROUND: This qualitative, exploratory study examines the content of communication between healthcare providers (HCP) and childhood cancer patients (CCP) during a medical appointment to evaluate the extent to which cancer survivorship issues (medical and psychosocial) are discussed. METHODS: The content of the communication for 16 CCP ages 10-22 and their HCP were examined via audio recorded medical appointments occurring within 6 months of the end of active cancer treatment. The data were analysed using template analysis, a constructivist-interpretivist qualitative approach. RESULTS: HCP addressed more medically focused than psychosocially focused issues related to survivorship. CONCLUSIONS: Most discussions of survivorship are medically focused, potentially leaving patients with little information about future psychosocial functioning. Recommendations for future research on enhancing discussions about psychosocial issues are presented. This research has the potential to inform future interventions to enhance patient-provider communication on survivorship issues.

Sensitivity of hematological malignancies to graft-versus-host effects: an EBMT megafile analysis.

After allogeneic stem cell transplantation, graft-versus-host disease (GvHD) occurs through recognition of histocompatibility mismatches by donor T lymphocytes. The same mechanism operates in eliminating malignant cells (the graft-versus-tumor or GvT effect). We hypothesized that comparing the correlation between GvHD and relapse might provide a surrogate marker for the susceptibility of diseases to allo-immune effects. We studied 48 111 first allogeneic transplants performed between 1998 and 2007. In chronic myeloid leukemia (CML), the relapse risk declined clearly and proportionally to severity of acute and chronic GvHD. Acute lymphoblastic leukemia and BCR-ABL-negative myeloproliferative neoplasias were comparably sensitive to GvHD as CML, whereas myelodysplastic syndromes and lymphoproliferative disorders showed intermediate sensitivity. GvHD was only associated with modest reductions in relapse risk in acute myeloid leukemia (AML) and plasma cell disorders (PCDs). Except for PCD, hazard rates for relapse decreased to almost 0 at 48 months of follow-up in all diseases. These data confirm observations of potent GvT effects associated with GvHD. The strength of the GvHD/GvT correlation differs significantly between hematological malignancies. The parallel drop of relapse rates in different diseases despite differences in GvHD/GvT ratios suggests that GvT effects might operate in the absence of GvHD, particularly in AML.

The impact of T-cell depletion techniques on the outcome after haploidentical hematopoietic SCT.

Several T-cell depletion (TCD) techniques are used for haploidentical hematopoietic SCT (HSCT), but direct comparisons are rare. We therefore studied the effect of in vitro TCD with graft engineering (CD34 selection or CD3/CD19 depletion, 74%) or in vivo TCD using alemtuzumab (26%) on outcome, immune reconstitution and infections after haploidentical HSCT. We performed a retrospective multicenter analysis of 72 haploidentical HSCT in Switzerland. Sixty-seven patients (93%) had neutrophil engraftment. The 1-year OS, TRM and relapse incidence were 48 (36-60)%, 20 (11-33)% and 42 (31-57)%, respectively, without differences among the TCD groups. In vivo TCD caused more profound lymphocyte suppression early after HSCT, whereas immune recovery beyond the second month was comparable between the two groups. Despite anti-infective prophylaxis, most patients experienced post-transplant infectious complications (94%). Patients with in vivo TCD had a higher incidence of CMV reactivations (54% vs 28%, P=0.015), but this did not result in a higher TRM. In conclusion, TCD by graft engineering or alemtuzumab are equally effective for haploidentical HSCT.