KRD (carfilzomib and lenalidomide plus dexamethasone) for the treatment of relapsed or refractory multiple myeloma in the real-life: a retrospective survey in 123 patients.

From April 2016, carfilzomib, in combination with lenalidomide and dexamethasone (KRD), became available for use in the daily practice in Italy for patients with relapsed or refractory multiple myeloma (RRMM). We performed a retrospective survey at 14 different institutions from Southern Italy in order to evaluate patient characteristics and treatment results from an unselected series of patients treated accordingly so far. One hundred and twenty-three consecutive patients were included, with a median of 2 previous lines of therapy (range 1-9) and a median age of 63 years (range 39-82). At the time of analysis, median number of courses administered is 11 (range 1-34), and all patients are evaluable for response. Overall response rate including complete remission, very good partial remission, and partial remission is 85%. After a median follow-up of 27 months, median overall and progression-free survival are 33 and 23 months, respectively. Sixty-three patients are alive and between them, 45 (37%) are in continuous remission. Sixty patients have died (49%), mainly from progressive disease. There were 6 treatment-related deaths (5% of the whole patient population). Overall, hematological and non-hematological toxicity were manageable, mostly on outpatient basis. Arterial hypertension has been observed in 43 cases (35%) but did not lead to treatment interruption. Our data demonstrate that in real life, KRD is highly effective and well tolerated in the majority of patients with RRMM.

Kidney Intragraft Homing of De Novo Donor-Specific HLA Antibodies Is an Essential Step of Antibody-Mediated Damage but Not Per Se Predictive of Graft Loss.

Donor-specific HLA antibody (DSA)-mediated graft injury is the major cause of kidney loss. Among DSA characteristics, graft homing has been suggested as an indicator of severe tissue damage. We analyzed the role of de novo DSA (dnDSA) graft homing on kidney transplantation outcome. Graft biopsy specimens and parallel sera from 48 nonsensitized pediatric kidney recipients were analyzed. Serum samples and eluates from graft biopsy specimens were tested for the presence of dnDSAs with flow bead technology. Intragraft dnDSAs (gDSAs) were never detected in the absence of serum dnDSAs (sDSAs), whereas in the presence of sDSAs, gDSAs were demonstrated in 72% of biopsy specimens. A significantly higher homing capability was expressed by class II sDSAs endowed with high mean fluorescence intensity and C3d- and/or C1q-fixing properties. In patients with available sequential biopsy specimens, we detected gDSAs before the appearance of antibody-mediated rejection. In sDSA-positive patients, gDSA positivity did not allow stratification for antibody-mediated graft lesions and graft loss. However, a consistent detection of skewed unique DSA specificities was observed over time within the graft, likely responsible for the damage. Our results indicate that gDSAs could represent an instrumental tool to identify, among sDSAs, clinically relevant antibody specificities requiring monitoring and possibly guiding patient management.

Posttransplant de novo donor-specific hla antibodies identify pediatric kidney recipients at risk for late antibody-mediated rejection.

The emerging role of humoral immunity in the pathogenesis of chronic allograft damage has prompted research aimed at assessing the role of anti-HLA antibody (Ab) monitoring as a tool to predict allograft outcome. Data on the natural history of allografts in children developing de novo Ab after transplantation are limited. Utilizing sera collected pretransplant, and serially posttransplant, we retrospectively evaluated 82 consecutive primary pediatric kidney recipients, without pretransplant donor-specific antibodies (DSA), for de novo Ab occurrence, and compared results with clinical-pathologic data. At 4.3-year follow up, 19 patients (23%) developed de novo DSA whereas 24 had de novo non-DSA (NDSA, 29%). DSA appeared at a median time of 24 months after transplantation and were mostly directed to HLA-DQ antigens. Among the 82 patients, eight developed late/chronic active C4d+ antibody-mediated rejection (AMR), and four C4d-negative AMR. Late AMR correlated with DSA (p < 0.01), whose development preceded AMR by 1-year median time. Patients with DSA had a median serum creatinine of 1.44 mg/dL at follow up, significantly higher than NDSA and Ab-negative patients (p < 0.005). In our pediatric cohort, DSA identify patients at risk of renal dysfunction, AMR and graft loss; treatment started at Ab emergence might prevent AMR occurrence and/or progression to graft failure.

Detection of GD2-positive cells in bone marrow samples and survival of patients with localised neuroblastoma.

The impact of bone marrow (BM) GD2-positive cells on survival has been evaluated in 145 Italian children with localised neuroblastoma (NB) evaluated at diagnosis by anti-GD2 immunocytochemistry. Nineteen of these (13.1%) were found to be BM GD2-positive, with the number of positive cells ranging between 1 and 155 out of 1 x 10(6) total cells analysed. Seven/19 (38.8%) GD2-positive vs 12/126 (9.5%) GD2-negative patients relapsed. The 5-year event-free survival (EFS) and overall survival of the GD2-positive patients was significantly worse than that of the GD2-negative ones (62.2 vs 89.9%, P<0.001; and 74.9 vs 95.9%, P=0.005, respectively). GD2 positivity was not associated to other known risk factors, and in particular to Myc-N amplification and 1p deletion. Among Myc-N-negative patients, the EFS of those negative for both GD2 and 1p deletion was significantly better than in children positive for either one of these two markers (EFS=96.9 vs 66.0%, P<0.001). In conclusion, GD2 positivity may represent a prognostic marker for patients with non-metastatic NB without Myc-N amplification, and its combination with genetic alterations might help identifying patients that require a more careful follow-up.

[Gastric fibroid polyp in a 4-month-old girl with Costello syndrome]. / Polipo fibroide gastrico in sindrome di Costello.

We describe the case of a 4-month-old girl with a gastric fibroid polyp. This was an occasional radiographic finding, confirmed by sonography and computerized tomography. This very rare benign tumor was surgically removed. The diagnosis of Costello syndrome was based on clinical appearance. This is the first report of a gastric fibroid polyp in Costello syndrome, a genetic disease with a high tumor frequency.

Multimodal imaging in the congenital pulmonary lymphangiectasia-congenital chylothorax-hydrops fetalis continuum.

We report on three infants with congenital chylothorax (CC) and congenital pulmonary lymphangiectasia (CPL). CPL appears to be a characteristic pathological finding in CC. Through the use of lymphoscintigraphy and computed tomography, this study suggests that CC and CPL are strongly correlated entities and that the dysplasia of the lymphatic system results in a pulmonary lymphatic obstruction sequence. The initial microscopic dilatation of the lymph channels may lead to progressive weeping of lymphatics and, consequently, to pleural effusion. Non-Immune Hydrops Fetalis (NIHF) may be the final consequence of impaired systemic venous return and may help to explain pleural-pulmonary involvement in this generalized lymph-vessel malformation syndrome.

[A case of pediatric ganglioneuroma with second tumor nine years later]. / Un caso di ganglioneuroma (GN) in età pediatrica con seconda neoplasia a nove anni di distanza.

The Authors describe the case of a 8-y female with an abdominal GN who developed nine years later an ovarian tumor. This association is an unusual and noteworthy event.

Persistence of Müllerian derivatives and intestinal lymphangiectasis in two newborn brothers: confirmation of the Urioste syndrome.

We describe two newborn brothers with a pattern of malformation characterized by the persistence of Müllerian duct derivatives, intestinal lymphangiectasia, hypertrophied alveolar ridges, and early death. Postmortem examination showed the presence of a rudimentary uterus, fallopian tubes, the upper third of a vagina, a prostate of normal shape, a dilated colon, and generalized intestinal and pulmonary lymphangiectasia. The syndrome was first delineated by Urioste and co-workers [1993: Am J Med Genet 47:494-503]. These cases confirm the existence of a definite and distinct entity.

Intercellular adhesion molecule-1 (ICAM-1) and granulocyte-macrophage colony stimulating factor (GM-CSF) co-expression in cutaneous malignant melanoma lesions.

The expression of intercellular adhesion molecule-1 (ICAM-1) and granulocyte-macrophage colony stimulating factor (GM-CSF) was investigated in 25 melanoma patients by evaluating 34 fresh biopsy specimens. ICAM-1 in situ hybridization and immunochemistry for ICAM-1 and GM-CSF were performed. Most of the metastatic melanoma samples (12 out of 18) and a few of the primary melanoma lesions (three out of 16) showed ICAM-1 expression. The expression of ICAM-1 was significantly (P < 0.01) higher in metastatic lesions than in primary tumours. GM-CSF mRNA and protein were detected in 10 of the 18 metastatic samples and in two of the 15 primary lesions. A significantly high degree (P < 0.0002) of concordance between ICAM-1 and GM-CSF expression was observed: the samples that were negative or positive for ICAM-1 expression were correspondingly negative or positive for GM-CSF. Correlation with clinical and histological parameters was examined. The expression of both molecules in metastatic samples was found to be significantly (P < 0.001) associated with a shorter recurrence-free period. These findings, if confirmed by a wider number of patients, could suggest the prognostic value of the simultaneous, and probably co-ordinated, expression of ICAM-1 and GM-CSF. They also highlight the importance of preventive molecular and biochemical characterization of neoplastic cell cytokine receptors, specifically focusing on the particular cytokine to be used as anticancer therapy and/or as adjunct to chemotherapy.

Conventional isolated hyperthermic antiblastic perfusion in the treatment of recurrent limb melanoma.

Hyperthermic Antiblastic Perfusion (HAP) is a widely used method for the treatment of recurrent limb melanoma. In terms of tumor response, locoregional control and survival HAP has led to better results than those achieved with any other treatment. The aim of this report is to analyze our own experience with HAP in locally advanced limb melanoma. Thirty-two patients were submitted to HAP. HAP lasted 60 minutes, with maximal local temperature of 40.5-42 degrees C using melphalan 10 mg/L limb volume as antiblastic agent. Twenty patients had in-transit metastases and 12 local recurrence. Regional nodes were involved in 12 patients. Systemic leakage monitored with 125I or 99Tc ranged between 5-30% (mean 14%). No operative mortality nor major complications occurred. Local toxicity scored Wieberdink grade I in 8 patients, grade II in 17, grade III in 6 and grade IV in 1 case. Response rate (UICC) in the 16 patients treated with unexcised lesions was 94% (56% complete responses). With a median follow-up of 29 months (2-126) 14 patients relapsed after a median time of 10 months, and 17 patients are currently disease free, 3 of these are being reexcised and 3 re-perfused. Actuarial 5 years survival was 64%, with 39% disease free to the first relapse. Our results are consistent with the literature indicating HAP as a safe procedure with a high evidence of clinical responses.

Glucose phosphate isomerase (GPI) "Morcone": a new variant from Italy.

Here we report the 4th Italian case of glucose phosphate isomerase (GPI) deficiency. The propositus is a young man suffering from chronic haemolytic anaemia since birth with occasional transfusion requirement. Biochemical characterization of the defective enzyme revealed increased affinity for F-6-P, decreased affinity for G-6-P and marked thermoinstability. Electrophoretic mobility appeared normal. GPI from both parents showed similar but less pronounced biochemical alterations. The variant described here seems to be different from those previously reported. Thus, we propose the provisional name of GPI "Morcone".

Nucleolar organizer regions (NORs) in normal and pathological liver: a quantitative analysis.

By means of a silver staining method, Nucleolar Organizer Region-associated proteins (NORs) have been evaluated on paraffin sections of a series of 58 ultrasound-guided liver biopsy specimens. These included 12 normal livers, 12 cirrhotic livers, 12 cases of chronic hepatitis and 22 cases of hepatocellular carcinoma. A significant difference (P less than 0.001) was found between the mean AgNOR scores of the normal and pathological biopsies, and between the non-neoplastic and the carcinomatous lesions. The authors suggest that AgNOR counts, in combination with conventional histocytological criteria, may be a useful method in the diagnosis of liver diseases.

Nucleolar organizer regions and Ki-67 immunostaining in ductal breast cancer: a comparative study.

53 cases of invasive ductal (NOS) carcinomas of the breast were studied by means of an immunostaining method with Ki-67 monoclonal antibody and an argyrophilic method for the demonstration of Nucleolar Organizer Regions (AgNORs). The percentage of cancer cells with nuclear Ki-67 immunoreactivity and the mean number of NORs for each tumour were statistically related. The data obtained showed a good correlation between Ki-67 index and NOR score (rS = 0.47 - P less than 0.001). The authors suggest that the AgNOR method--which is applicable to routinely processed material--might effectively substitute Ki-67 immunostaining as a marker of cell proliferation in ductal breast cancer.