Abstract
Background and Aims
Efficacy of acute rejection (AR) therapy has always been evaluated based upon improvement of renal function. On the contrary, the degree of histological lesion (HL) ...regression has rarely been considered for this purpose.
The main goal of this study was to evaluate the percentage of failures in HLs regression after treatment aimed at both “subclinical” and “clinical” AR. Treatment efficacy was therefore evaluated with control renal biopsies (CBs) performed 30-60 days after anti-rejection therapy. In addition, the correlation between graft function and histological data was assessed. The results of treatment for “subclinical" and "clinical” AR were considered separately.
Method
Real-time ultrasound-guided CBs were performed in an outpatient setting using 16G tru-cut needles. The HLs considered were: interstitial inflammation (i), tubulitis (t), glomerulitis (g), arteritis (v), capillaritis (ptc). Each lesion was graded from 0 to 3 (sec Banff 2013-2017). For this study, only HLs with a score ≥2 were considered. Therapy failure was determined both by the percentage of patients (pts) with persistence of HLs and by the change of HLs score after treatment, in the control biopsies. Anti-rejection therapy varied according to AR type and severity. In patients failing AR therapy, serum creatinine was evaluated before and after the treatment.
Results
111 BCs were performed after treatment either for subclinical (n = 47) or for clinical (n = 64) AR. Before therapy, HLs (with score ≥2) present in subclinical and clinical AR were: i: 23% and 52%; t: 30% and 30%; g: 34% and 41%; ptc: 11% and 28%; v: 15% and 19%.
After therapy, in the setting of subclinical AR, HLs were still present with a range between 29% (v) and 81% (g) with stable or improved histological score. In this scenario, renal function resulted stable and satisfactory (Tab 1).
In the case of clinical AR, the persistence of histological lesions ranged from 25% (v) to 92% (g), also with stable or improved histological scores. In this case, therapy was always followed by an improvement in renal function (Tab 2).
Conclusion
After AR therapy, only the morphological data obtained with histological analysis can disclose failures of anti-rejection therapy, both in presence of subclinical and clinical AR.
The high rate of treatment failure may explain the correlation between AR and worse graft survival.
Our results could lead us to consider the need for a more aggressive anti-rejection treatment.
Control renal biopsies after AR therapy should always be considered on clinical grounds.
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Abstract
Context
Apo A-I Leu75Pro is a rare hereditary form of amyloidosis that mainly involves the kidney, the liver, and the testis.
Objective
To define the characteristics of organ damage and ...testis impairment in the largest cohort collected to date of men with Apo A-I Leu75Pro amyloidosis.
Design, Setting, and Patients
Retrospective study from a prospectively collected database of 129 male subjects >18 years with Apo A-I Leu75Pro amyloidosis from a reference center at the University Hospital of Brescia, Italy.
Main outcome measures
We evaluated liver and renal function, scrotal ultrasound, reproductive hormone levels, testis biopsy, hypogonadal symptoms, and fertility.
Results
Progressive involvement of testis, kidney, and liver was observed in 96/129 (74.4%) cases. Testis impairment was found in 88/129 patients (68.2%), liver in 59 (45.7%) and renal in 50 (38.8%). Testis damage was often the first manifestation of the disease and the only dysfunction in 30% of younger patients (<38 years). Testicular involvement was characterized mainly by primary (73/88 patients, 83.0%) and subclinical (8/88, 9.1%) hypogonadism. Almost all (85/88, 96.6%) also had high follicle-stimulating hormone, suggesting a primary global damage of endocrine and spermatogenic functions, and 30% of them did not conceive. Macroorchidism was found in 53/88 (60.2%) patients, especially in men <54 years (30/33, 90.9%). Apo A-I amyloid deposits were found in Sertoli cells, germinal epithelium, and vessel walls.
Conclusion
In men with Apo A-I Leu75Pro amyloidosis, testicular involvement is the hallmark of the disease, characterized by global primary testicular dysfunction and macroorchidism due to amyloid deposits.
Recently cabozantinib, a tyrosine kinase inhibitor with activity against VEGF, MET, AXL, and downregulating cathepsin K in vitro, has been proposed for the treatment of advanced clear and non-clear ...renal cell carcinomas. Since it is well known that cathepsin K is expressed in the majority of MiT family translocation renal cell carcinomas, we investigated cathepsin K, MET, AXL, and VEGF in a large series of those tumours, looking for possible predictive markers. We collected the clinicopathological features of 34 genetically confirmed MiT family translocation renal cell carcinomas 26 Xp11 and 8 t(6;11) renal cell carcinomas and studied them using an immunohistochemical panel including PAX8, cathepsin K, HMB45, Melan-A, CD68 (PG-M1), CK7, CA9, MET, AXL and by FISH for VEGFA and MET. Cathepsin K was expressed in 14 of 26, HMB45 in 8 of 25, and Melan-A in 4 of 23 Xp11 renal cell carcinomas, whereas labelling for CK7 and CA9 was minimal. In t(6;11) renal cell carcinoma, cathepsin K and melanogenesis markers were constantly positive, whereas CK7 and CA9 were negative. None of the 34 carcinomas showed CD68 (PG-M1) and AXL expression. One aggressive Xp11 renal cell carcinoma showed increased VEGFA gene copy number (4–5 copies) with concurrent gains of TFE3 and TFEB. None of the 34 carcinomas showed MET gene amplification, whereas staining for MET was found in 7 of 8 t(6;11) and in 16 of 24 Xp11 renal cell carcinomas, and in the latter cases, when the expression was >50%, correlated with aggressiveness (p=0.0049). In Xp11 renal cell carcinomas, the aggressiveness was also correlated with larger tumour size (p=0.0008) and the presence of necrosis (p=0.027) but not nucleolar grading (p=1). Interestingly, in patients with tumours exhibiting two of three parameters (necrosis, larger tumour size and MET immunolabelling >50%) an aggressive clinical behaviour was observed in 88% of cases. In conclusion, cathepsin K, CD68 (PG-M1), CK7, CA9, and PAX8 is a useful panel for the diagnosis. Larger tumour size, the presence of necrosis and MET immunohistochemical expression correlate with aggressive behaviour in Xp11 renal cell carcinomas, especially in combination. VEGF, MET, cathepsin K but not AXL may be potential predictive markers for targeted therapy in MiT family translocation renal cell carcinomas.
The role of positive surgical margins (PSMs) on the recurrence of renal cell carcinoma (RCC) after partial nephrectomy (PN) is debated, and available evidence lacks long-term data. The aim of this ...study was to evaluate the predictive role of PSMs on progression-free survival (PFS) in a large cohort followed for at least 5 years.
This study was a retrospective analysis of a prospectively compiled single-institution database collecting complete information on more than 2700 patients who had undergone surgery for renal tumor. The data of all the patients submitted to PN for RCC and with least 5 years follow-up were extracted. Surgical specimens were examined at the time of surgery only by 2 expert uro-pathologists. A PSM was defined as the presence of cancer cells at the inked surface of the specimen. The role of PSMs on survival was estimated by Cox regression models adjusted for influent covariates.
A total of 459 patients fulfilled the inclusion criteria and were evaluated. PSMs were observed in 27 (5.9%) cases. No differences in preoperative and pathologic data were found comparing patients with and without PSMs. At a median follow-up of 96 months (interquartile range, 74-131 months), a clinically evident relapse of RCC was diagnosed in 36 (7.8%) patients at a median interval of 36 months from PN. Among these, 6 had a PSM for an incidence of relapse of 22.2% in the PSM group, whereas 30 had negative margins, for an incidence of 6.9% (P = .013). The sites of relapse were distant organs in 18 cases, and the kidney underwent PN in 21. The patients with PSMs showed a borderline significantly higher incidence of distant metastasis (11.1% vs. 3.5%; P = .071) and a significantly higher incidence of renal relapses (14.8% vs. 3.9%; P = .029). Multivariable Cox models confirmed that the presence of PSMs was an independent predictor of PFS (odds ratio, 3.127; P = .013).
PSMs are an independent predictor of PFS in patients who underwent PN for RCC, owing to a higher incidence of distant and local relapses. Surveillance in presence of PSMs should be intensified and extended for a long time.
The presence of positive surgical margins (PSMs) after partial nephrectomy has been associated with an increased risk of disease recurrence, but conclusive evidence is lacking. The aim of this study is to examine the prognostic role of PSMs in a large retrospective cohort with long-term follow-up. PSMs were associated with disease recurrence, both local and distant, and decreased progression-free survival. Patients with PSMs should undergo a more intense follow-up.
Background. We recently reported that Circulating Endothelial Cell (CEC) count changes represent a promising marker to monitor endothelial damage in patients undergoing allogeneic hematopoietic stem ...cell transplant (allo-HSCT), potentially becoming a valuable tool in the diagnostic definition of GVHD. Besides confirming an increase of CEC counts at GVHD onset, we repeatedly documented at time of engraftment statistically significant higher numbers of CEC in patients who will not manifest GVHD in comparison to patients in which GVHD will be diagnosed (Transplantation 2014,98:706-12; Bone Marrow Transplantation 2017,52:1637-42; Scientific Reports 2019,9:1-12). Recent knowledges in organ transplant pointed out that endothelial cells from the grafted organ, besides being a continuous source of alloantigens, can downregulate alloreactivity exerting tolerogenic responses. By inference to the allo-HSCT field, it could be envisaged that presence of donor CEC could induce protective effects on alloreactivity.
Methods. We planned a study to test the hypothesis that at time of engraftment, CEC present in peripheral blood (PB), besides coming from cells shedding from patient vasculature, could partly belong to donor, originating from the cellular graft. Therefore, in an exploratory set, we performed FISH analysis on flowcytometry-sorted CEC (CD45neg/CD34bright/CD146pos, Lyotube #623920, BD Biosciences) (n=3) and on whole PB derived culture-expanded CEC (n=3) (EGM-2 BulletKit, Lonza), obtained at engraftment in sex-mismatched allo-HSCT. In the confirmatory set (n=15), single CEC were recovered from PB, at engraftment (T1) and at 90 days (T2) after allo-HSCT, through the DEPArrayTM technology (Menarini Silicon Biosystems), after preliminary bulk separation step carried out with the CellSearch® System. Single recovered CEC was whole genome amplified (Ampli1™ WGA Kit) and short tandem repeat (STR) profile determined (Ampli 1TM STR kit) on each single CEC. To confirm host/donor origin, single CEC STR profile was compared to that determined on patient and donor cells before allo-HSCT. Moreover, donor CEC presence was evaluated by CISH analysis on formaline fixed and paraffin-embedded biopsy sections obtained at least three months after sex mismatched allo-HSCT.
Results. By positive findings of the exploratory set, we proved, at the single cell level in the confirmatory set, the presence of donor CEC at engraftment (T1) in 4 out of 15 patients (Table 1). Of them, 2 did not manifested GVHD, despite a GVHD risk score of 2, and the other 2 presented GVHD grade I. On the contrary, among the 10 patients in whom no donor CEC were detected, 6 experienced GVHD grade II-III, while 4 did not manifested GVHD, despite a 1-3 GVHD risk score.
Conclusions. Our data represent the proof of principle that donor CEC may flow in host PB early on from hematopoietic recovery and seldom persist thereafter at steady-state conditions, being potentially embedded in host vascular wall. These puzzling findings suggest that neovascularization takes place in parallel with hematopoietic engraftment and could provide further clues on shedding light on tissue tolerance in the context of GVHD, opening up paradoxical scenarios on the protective role potentially played by donor CEC.
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Fontana:Menarini Silicon Biosystem: Employment. Rotta:BD Biosciences Italia: Employment. Manaresi:Menarini SIlicon Biosystem: Employment, Membership on an entity's Board of Directors or advisory committees.
Although diffuse large B cell lymphoma (DLBCL) is considered a curable disease in the immunochemotherapy (ICT) era, about 40% of patients relapse or are refractory to first line treatment, ...representing an unmet clinical need. The role of upfront autotransplantation (ASCT) in high-risk cases is still debated, while its role in relapsed/refractory (R/R) disease is established in all guidelines. However less than 50% are actually cured with salvage ASCT (Gisselbrecht C et al, J Clin Oncol. 2010) and outcome of patients who relapse after ASCT is very poor (Crump M. et al, Blood 2017; Van Den Neste E et al, BMT 2017). Prognosis of aggressive lymphomas with characteristics intermediate with Burkitt's lymphoma (BCLU), recently reclassified (WHO 2016) as high grade lymphoma, unspecified with or without c-myc translocation, is less favourable. Regimens containing HD-MTX/ARA-C were generally used to treat these lymphoma subtypes as well as lymphoma with central nervous system (CNS) localization. Aim of this study was to evaluate the prevalence and outcome of R/R lymphoma after upfront or salvage ASCT or after HD-MTX/ARA-C regimens in the clinical care setting and to identify potential salvage approaches.
We retrospectively analysed all consecutive HIV-negative patients seen at our Institute from January 2008 to December 2016 with de novo or transformed DLBCL, Primary mediastinal B-cell lymphoma or high-grade lymphoma/BCLU. First-line treatment used was R-CHOP/CHOP-like regimens. Consolidation with ASCT was performed in all high/intermediate-high IPI risk patients less than 65 years old, while salvage ASCT was performed after salvage ICT for R/R disease; HD-MTX/ARA-C regimens were used in DLBCL patients with CNS involvement or in BCLU cases. Relapsed or refractory patients after upfront or salvage ASCT or after HD-MTX/ARA-C were selected and their demographic and histological features as well as their outcome was analysed in term of duration of Response (DOR) from ASCT or MTX/ARA-C regimen to relapse and Overall Survival (OS) from relapse to the last follow-up or death. We recorded salvage treatments carried out according to age, performance status, available clinical protocols or international guidelines (more than one line in some patients).
RESULTS: Among 571 patients consecutively seen during the time period, 156 (27.3%) proved refractory or relapsed after first-line treatment. ASCT was performed in 86 patients as consolidation (group A) and in 33 as salvage (group B). First line HD-MTX/ARA-C regimens were used in 16 patients (group C). Relapse occurred in 9/86 group A (10%), 20/33 group B (61%) and 8/16 group C (50%) patients respectively, representing 6.5% of the whole patients initially diagnosed. First relapse occurred after a median DOR of 4, 7, and 3.5 months in group A, B and C respectively. The main demographic and histological characteristics of relapsed patients are summarized in the Table 1, which also shows treatments used after relapse. Response rates in patients treated with curative intent were 29% (6/21). Mortality rates were high in all groups (78%, 90% and 100% respectively), with an OS significantly better in group A comparing to group B and C patients (p 0.0243) (Fig.1a) and in patients treated with curative intent compared to patients that received palliation (p <0.0001) (Fig.1b). Four patients only are currently alive, 2 in group A at 84 and 3 months after allotransplantation and 2 in group B at 15 months after HD-MTX/ARA-C for CNS recurrence and after R-DHAP ICT with lenalidomide maintenance still ongoing at month 36th as part of a study protocol. The cause of death for all patients was progression of disease.
This analysis shows the very poor prognosis of patients with aggressive lymphoma relapsing after high dose therapy (ASCT or MTX/ARA-C). The recurrence of disease in these patients is early and salvage therapies are ineffective in most of the cases, although trying to treat these patients with curative intent shows a survival advantage over palliation. Patients treated with multiple lines of chemotherapy (group B) or with upfront HD-MTX/ARA-C (group C) have the worse prognosis. These data justify intensive follow-up programs during the first year after the end of therapy, and underline the need to develop new therapeutic strategies for this setting of patients, which could represent an ideal indication for CAR-T cell treatments.
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Rossi:GILEAD: Other: ADVISORY BOARD; SANOFI: Other: ADVISORY BOARD; NOVARTIS: Honoraria; ABBVIE: Other: ADVISORY BOARD; CELGENE: Other: ADVISORY BOARD; AMGEN: Other: ADVISORY BOARD; JAZZ: Other: ADVISORY BOARD; JANNSEN: Other; MUNDIPHARMA: Honoraria; BMS: Honoraria; PFIZER: Other: ADVISORY BOARD; TEVA: Other: ADVISORY BOARD; ROCHE: Other: Advisory Board; SANDOZ: Honoraria.
Molluscum contagiosum virus (MCV) infection induces self-limiting cutaneous lesions in an immunocompetent host that can undergo spontaneous regression preceded by local inflammation. On histology, a ...large majority of MCV-induced lesions are characterized by islands of hyperplastic epithelium containing infected keratinocytes and surrounded by scarce inflammatory infiltrate. However, spontaneous regression has been associated with the occurrence of a dense inflammatory reaction. By histology and immunohistochemistry, we identified MCV-induced lesions showing a dense inflammatory infiltrate associated with cell death in keratinocytes (inflammatory Molluscum contagiosum (I-MC)). In I-MC, hyperplastic keratinocytes were highly immunogenic as demonstrated by the expression of major histocompatibility complex class I and II molecules. Immune cell infiltration consisted of numerous cytotoxic T cells admixed with natural killer cells and plasmacytoid dendritic cells (PDCs). Accordingly, a type I IFN signature associated with PDC infiltration was demonstrated in both keratinocytes and inflammatory cells. Among the latter, a cell population resembling IFN-DC (CD123+CD11c+CD16+CD14+MxA+) was identified in proximity to islands of apoptotic keratinocytes. In vitro–generated IFN-DCs expressed a strong cytotoxic signature, as demonstrated by high levels of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and Fas ligand (FasL). This study establishes a previously unreported model to underpin the role of innate immune cells in viral immune surveillance.
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