T-Cells Subsets in Castleman Disease: Analysis of 28 Cases Including Unicentric, Multicentric and HHV8-Related Clinical Forms.

Castleman disease (CD) is a rare lymphoproliferative disorder that includes various clinico-pathological subtypes. According to clinical course, CD is divided into unicentric CD (UCD) and multicentric CD (MCD). MCD is further distinguished based on the etiological driver in herpes virus-8-related MCD (that can occur in the setting of HIV); in MCD associated with POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes); and idiopathic MCD (iMCD). The latter can also be divided in iMCD-TAFRO (thrombocytopenia, anasarca, fever, myelofibrosis, organomegaly) and iMCD not otherwise specified. To date, CD pathogenesis is still uncertain, but CD may represent the histological and clinical result of heterogeneous pathomechanisms. Transcriptome investigations in CD lymph nodes have documented the expression and up-regulation of different cytokines; furthermore, few recent studies have shown alterations of different T-cell subsets in CD patients, suggesting a possible role of the nodal microenvironment in CD development. On this basis, our study aimed to investigate the distribution of T-cell subsets in the clinico-pathological spectrum of CD. We evaluated the CD4/CD8 ratio and the number of T-regulatory (T-reg) FOXP3+ cells in 28 CD cases. In total, 32% of cases showed a decreased CD4/CD8 ratio due to increased CD8+ T-cells, including both UCD, iMCD, and HHV8+ MCD cases. The T-reg subset analysis revealed a statistically significant (p < 0.0001) lower mean number of FOXP3+ T-reg cells in CD cases when compared with non-specific reactive lymph nodes. We did not find statistically significant differences in T-reg numbers between the different CD subtypes. These findings may suggest that alterations in T-cell subpopulations that can lead to disruption of immune system control may contribute to the numerous changes in different cellular compartments that characterize CD.

Once weekly versus twice weekly carfilzomib dosing in patients with relapsed and refractory multiple myeloma (A.R.R.O.W.): interim analysis results of a randomised, phase 3 study.

BACKGROUND: Twice a week carfilzomib at 27 mg/m2 is approved for treatment of relapsed or refractory multiple myeloma. Phase 1/2 CHAMPION-1, the first study exploring once-weekly carfilzomib dosing, established the maximum tolerated dose at 70 mg/m2 in combination with dexamethasone. We aimed to compare progression-free survival in patients with relapsed and refractory multiple myeloma given once weekly carfilzomib or twice weekly carfilzomib. METHODS: In this prespecified interim analysis of the randomised, open-label, phase 3 A.R.R.O.W. trial, we recruited patients (aged 18 years and older) with relapsed and refractory multiple myeloma previously treated with two or three treatments, including a proteasome inhibitor and immunomodulatory agent, from hospital, clinic, oncology or medical centres. Key eligibility criteria were refractory to most recent therapy (including bortezomib or ixazomib) with measurable disease, and Eastern Cooperative Oncology Group Performance Status of 0 or 1. Patients were randomly assigned (1:1) to receive carfilzomib once a week (70 mg/m2) or twice a week (27 mg/m2). The randomisation sequence was generated using a validated randomisation software and implemented using an interactive response technology system that assigned patients to treatment sequentially based on the randomisation sequence as patients were enrolled at participating clinical sites. Patients were stratified by International Staging System stage at study entry or baseline, whether or not they were refractory to bortezomib treatment, and age (block size of 4). The once weekly group received carfilzomib (30 min intravenous infusion) on days 1, 8, and 15 of all cycles (20 mg/m2 day 1 [cycle 1]; 70 mg/m2 thereafter). The twice weekly group received carfilzomib (10 min intravenous infusion) on days 1, 2, 8, 9, 15, and 16 (20 mg/m2 days 1 and 2 during cycle 1; 27 mg/m2 thereafter). All patients received dexamethasone (40 mg on days 1, 8, 15 [all cycles] and 22 [cycles 1-9 only]). Treatment continued until disease progression or unacceptable toxic effects. The primary objective was to compare progression-free survival between groups in the intention-to-treat population. Safety analysis was done in all randomly assigned patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT02412878, and is no longer enrolling patients. FINDINGS: Between September, 2015, and August, 2016, 578 patients were recruited from 118 sites. 478 patients were randomly assigned and included in the efficacy analyses (240 to receive once weekly carfilzomib; 238 to receive twice weekly carfilzomib). Median progression-free survival was higher in the once weekly group than the twice weekly group (11·2 months [95% CI 8·6-13·0] vs 7·6 months [5·8-9·2]; hazard ratio [HR] 0·69, 95% CI 0·54-0·83; p=0·0029). The incidence of grade 3 or worse adverse events was higher in the once weekly group than the twice weekly group (68% [n=161] vs 62% [n=145]); the most common events were anaemia, pneumonia, and thrombocytopenia (42 [18%] vs 42 [18%], 24 [10%] vs 16 [7%], and 17 [7%] vs 16 [7%], respectively for once weekly carfilzomib vs twice weekly carfilzomib). A lower proportion of patients had grade 3 or worse cardiac failure in the once weekly group (7 [3%]) than in the twice weekly group (10 [4%]). Treatment-related deaths occurred in five (2%) of 238 patients in the once weekly group (sepsis [n=1], death [n=1], acute lung injury [n=1], acute respiratory distress syndrome [n=1], and tumour lysis syndrome [n=1]) and in two (1%) of 235 patients in the twice weekly group (plasma cell myeloma [n=1] and congestive heart failure [n=1]). There were 58 deaths in the once weekly group and 68 deaths in the twice weekly group at the time of data cutoff. INTERPRETATION: Once weekly carfilzomib at 70 mg/m2 significantly prolonged progression-free survival versus the twice weekly schedule. Overall safety was comparable between the groups. Once weekly carfilzomib appears safe and more effective with a convenient dosing regimen versus the twice weekly schedule for the treatment of patients with relapsed and refractory multiple myeloma. FUNDING: Amgen, Inc.

A Multicenter Phase II Study of Twice-Weekly Bortezomib plus Rituximab in Patients with Relapsed Follicular Lymphoma: Long-Term Follow-Up.

Single-agent bortezomib (B) has shown activity in heavily pretreated patients with relapsed/refractory indolent lymphoma. On the basis of these findings, we performed a phase II study of B combined with rituximab (R) in patients with relapsed follicular lymphoma (FL). Forty-five patients with fairly good prognostic profiles were enrolled from 2007 to 2011 and received a total of 6 cycles of the B+R combination. The endpoints were the overall response rate (ORR), progression-free survival (PFS), duration of remission (DoR), overall survival (OS), and toxicity evaluation. When considering all the enrolled patients the ORR was 64%. At 5 years, the estimated PFS, DoR, and OS were 34, 49, and 70%, respectively. After excluding the 7 R-naïve patients, the ORR was 58%, with a PFS of 19 months. The most common grade >2 toxicities were thrombocytopenia (18%), peripheral neuropathy (13%), and neutropenia (2%). Our study shows the feasibility, long-term efficacy, and excellent tolerability of the B+R combination. We are aware that our study has specific limitations, such as the small sample size consisting of patients with a relatively good prognostic profile. However, because FL patients will be treated with subsequent chemotherapy regimens, a well-tolerated and effective chemotherapy-free therapy could be considered an additional tool for long-term disease control.

Bortezomib- and thalidomide-induced peripheral neuropathy in multiple myeloma: clinical and molecular analyses of a phase 3 study.

A subanalysis of the GIMEMA-MMY-3006 trial was performed to characterize treatment-emergent peripheral neuropathy (PN) in patients randomized to thalidomide-dexamethasone (TD) or bortezomib-TD (VTD) before and after double autologous transplantation (ASCT) for multiple myeloma (MM). A total of 236 patients randomized to VTD and 238 to TD were stratified according to the emergence of grade ≥2 PN. Gene expression profiles (GEP) of CD138+ plasma cells were analyzed in 120 VTD-treated patients. The incidence of grade ≥2 PN was 35% in the VTD arm and 10% in the TD arm (P < 0.001). PN resolved in 88 and 95% of patients in VTD and TD groups, respectively. Rates of complete/near complete response, progression-free and overall survival were not adversely affected by emergence of grade ≥2 PN. Baseline characteristics were not risk factors for PN, while GEP analysis revealed the deregulated expression of genes implicated in cytoskeleton rearrangement, neurogenesis, and axonal guidance. In conclusion, in comparison with TD, incorporation of VTD into ASCT was associated with a higher incidence of PN which, however, was reversible in most of the patients and did not adversely affect their outcomes nor their ability to subsequently receive ASCT. GEP analysis suggests an interaction between myeloma genetic profiles and development of VTD-induced PN.

Radial neck fractures in children: results when open reduction is indicated.

BACKGROUND: Radial neck fractures in children are rare, representing 5% of all elbow pediatric fractures. Most are minimally displaced or nondisplaced. Severely displaced or angulated radial neck fractures often have poor outcomes, even after open reduction, and case series reported in literature are limited. The aim of the study is to analyze the outcomes of patients with a completely displaced and angulated fracture who underwent open reduction when closed reduction failed. METHODS: Between 2000 and 2009, 195 patients with radial neck fractures were treated in our institute. Twenty-four cases satisfied all the inclusion criteria and were evaluated clinically and radiologically at a mean follow-up of 7 years. At follow-up, the carrying angle in full elbow extension and the range of motion of the elbow and forearm were measured bilaterally. We recorded clinical results as good, fair, or poor according to the range of movement and the presence of pain. Radiographic evaluation documented the size of the radial head, the presence of avascular necrosis, premature physeal closure, and cubitus valgus. RESULTS: Statistical analysis showed that fair and poor results are directly correlated with loss of pronation-supination (P = 0.001), reduction of elbow flexion-extension (P = 0.001), increase of elbow valgus angle (P = 0.002), necrosis of the radial head (P = 0.001), premature physeal closure (P = 0.01), and associated lesions (olecranon fracture with or without dislocation of the elbow) (P = 0.002). DISCUSSION: In our cases, residual radial head deformity due to premature closure of the growth plate and avascular necrosis were correlated with a functional deficit. Associated elbow injury was coupled with a negative prognosis. In our series, about 25% of patients had fair and 20% had poor results. Outcomes were good in 55% and felt to represent a better outcome than if the fracture remained nonanatomically reduced with residual angulation and/or displacement of the radial head. This study reports the largest series of these fractures with a combination of significant angulation and displacement of the fracture requiring open reduction. We feel that open reduction is indicated when the head of the radius is completely displaced and without contact with the rim of the metaphysis.

Melflufen or pomalidomide plus dexamethasone for patients with multiple myeloma refractory to lenalidomide (OCEAN): a randomised, head-to-head, open-label, phase 3 study.

BACKGROUND: Melphalan flufenamide (melflufen), an alkylating peptide-drug conjugate, plus dexamethasone showed clinical activity and manageable safety in the phase 2 HORIZON study. We aimed to determine whether melflufen plus dexamethasone would provide a progression-free survival benefit compared with pomalidomide plus dexamethasone in patients with previously treated multiple myeloma. METHODS: In this randomised, open-label, head-to-head, phase 3 study (OCEAN), adult patients (aged ≥18 years) were recruited from 108 university hospitals, specialist hospitals, and community-based centres in 21 countries across Europe, North America, and Asia. Eligible patients had an ECOG performance status of 0-2; must have had relapsed or refractory multiple myeloma, refractory to lenalidomide (within 18 months of randomisation) and to the last line of therapy; and have received two to four previous lines of therapy (including lenalidomide and a proteasome inhibitor). Patients were randomly assigned (1:1), stratified by age, number of previous lines of therapy, and International Staging System score, to either 28-day cycles of melflufen and dexamethasone (melflufen group) or pomalidomide and dexamethasone (pomalidomide group). All patients received dexamethasone 40 mg orally on days 1, 8, 15, and 22 of each cycle. In the melflufen group, patients received melflufen 40 mg intravenously over 30 min on day 1 of each cycle and in the pomalidomide group, patients received pomalidomide 4 mg orally daily on days 1 to 21 of each cycle. The primary endpoint was progression-free survival assessed by an independent review committee in the intention-to-treat (ITT) population. Safety was assessed in patients who received at least one dose of study medication. This study is registered with ClinicalTrials.gov, NCT03151811, and is ongoing. FINDINGS: Between June 12, 2017, and Sept 3, 2020, 246 patients were randomly assigned to the melflufen group (median age 68 years [IQR 60-72]; 107 [43%] were female) and 249 to the pomalidomide group (median age 68 years [IQR 61-72]; 109 [44%] were female). 474 patients received at least one dose of study drug (melflufen group n=228; pomalidomide group n=246; safety population). Data cutoff was Feb 3, 2021. Median progression-free survival was 6·8 months (95% CI 5·0-8·5; 165 [67%] of 246 patients had an event) in the melflufen group and 4·9 months (4·2-5·7; 190 [76%] of 249 patients had an event) in the pomalidomide group (hazard ratio [HR] 0·79, [95% CI 0·64-0·98]; p=0·032), at a median follow-up of 15·5 months (IQR 9·4-22·8) in the melflufen group and 16·3 months (10·1-23·2) in the pomalidomide group. Median overall survival was 19·8 months (95% CI 15·1-25·6) at a median follow-up of 19·8 months (IQR 12·0-25·0) in the melflufen group and 25·0 months (95% CI 18·1-31·9) in the pomalidomide group at a median follow-up of 18·6 months (IQR 11·8-23·7; HR 1·10 [95% CI 0·85-1·44]; p=0·47). The most common grade 3 or 4 treatment-emergent adverse events were thrombocytopenia (143 [63%] of 228 in the melflufen group vs 26 [11%] of 246 in the pomalidomide group), neutropenia (123 [54%] vs 102 [41%]), and anaemia (97 [43%] vs 44 [18%]). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]). 27 [12%] patients in the melflufen group and 32 [13%] in the pomalidomide group had fatal treatment-emergent adverse events. Fatal treatment-emergent adverse events were considered possibly treatment related in two patients in the melflufen group (one with acute myeloid leukaemia, one with pancytopenia and acute cardiac failure) and four patients in the pomalidomide group (two patients with pneumonia, one with myelodysplastic syndromes, one with COVID-19 pneumonia). INTERPRETATION: Melflufen plus dexamethasone showed superior progression-free survival than pomalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma. FUNDING: Oncopeptides AB.

Delayed complete repair of exstrophy with testosterone treatment: an alternative to avoid glans complications?

PURPOSE: Since 1999, complete primary repair of exstrophy has represented a valid alternative in the treatment of exstrophy patients, offering one- stage reconstruction for all components of this malformation in newborns. The vast majority of cases are currently approached within 48/72 h of life, and risk of vascular injury to penile glans and/or corpora has been reported with increased frequency with this procedure. We report our initial experience with a delayed approach to complete repair, with bladder plate left intact and taken care at home by the parents, while awaiting for the patient to reach adequate weight. Delayed approach also enabled us to preoperatively stimulate phallic size with testosterone, a treatment which was so far confined only to redo or failed cases. METHODS: Six male exstrophy patients were treated over a three-year (2007-2009) period. After initial workup, newborns were discharged home with bladder plate taken care by the parents. A weight of 4,500 g was arbitrarily deemed satisfactory for surgery. While at home, patients underwent preoperative testosterone stimulation (testosterone enanthate, four biweekly administrations of 100 mg/per square meter body surface). In each case biopsies of bladder mucosa were taken at time of surgery. Complications, age at surgery, increases in phallic size were extracted from clinical and surgical case notes. RESULTS: Weight at surgery ranged from 4,510 to 5,600 g. Age range was 43-91 days. Mean increase in phallic size after testosterone stimulation was 8.3 mm. Three complications were observed: two were suprapubic fistulas, of these, one closed spontaneously and one required surgery subsequently. In one fascial dehiscence emergency closure was needed. Hypospadias occurred in all patients. All histologic specimens demonstrated a mildly inflamed bladder mucosa. CONCLUSIONS: Delayed repair of bladder exstrophy allows to approach patients who have reached adequate weight and stabilization; if adequately cared for bladder plate shows minimal inflammation at surgery and can be managed by the parents at home. Deferring surgery also offers the advantages of preoperative testosterone stimulation, promotion of mother-baby relationship as well as of transfer to Centers with adequate experience and proficiency in all aspects of bladder exstrophy reconstruction.

Characteristics and outcomes of five patients with COVID-19 and hematological malignancies.

Patients with hematological cancer are at major risk of developing infectious complication. The prevention and treatment of COVID-19 in these patients is challenging. This experience, with the limitation of a small number of patients, highlights that early treatment of COVID-19 can overcome the infection, also in hematological patients.

Ultrasound-guided central venous catheterization in cancer patients improves the success rate of cannulation and reduces mechanical complications: a prospective observational study of 1,978 consecutive catheterizations.

BACKGROUND: A central venous catheter (CVC) currently represents the most frequently adopted intravenous line for patients undergoing infusional chemotherapy and/or high-dose chemotherapy with hematopoietic stem-cell transplantation and parenteral nutrition. CVC insertion represents a risk for pneumothorax, nerve or arterial punctures. The aim of this prospective observational study was to explore the safety and efficacy of CVC insertion under ultrasound (US) guidance and to confirm its utility in clinical practice in cancer patients. METHODS: Consecutive adult patients attending the oncology-hematology department were eligible if they had solid or hematologic malignancies and required CVC insertion. Four types of possible complication were defined a priore: mechanical, thrombotic, infection and malfunctioning. The patient was placed in Trendelenburg's position, a 7.5 MHZ puncturing US probe was placed in the supraclavicular site and a 16-gauge needle was advanced under real-time US guidance into the last portion of internal jugular vein. The Seldinger technique was used to place the catheter, which was advanced into the superior vena cava until insertion into right atrium. Within two hours after each procedure, an upright chest X-ray and ultrasound scanning were carried out to confirm the CVC position and to rule out a pneumotorax. CVC-related infections, symptomatic vein thrombosis and malfunctioning were recorded. RESULTS: From December 2000 to January 2009, 1,978 CVC insertional procedures were applied to 1,660 consecutive patients. The procedure was performed 580 times in patients with hematologic malignancies and 1,398 times those with solid tumors. A single-needle puncture of the vein was performed on 1,948 of 1,978 procedures (98.48%); only eighteen attempts among 1,978 failed (0.9%). No pneumotorax, no major bleeding, and no nerve puncture were reported; four cases (0.2%) showed self-limiting hematomas. The mean lifespan of CVC was 189.7 +/- 18.6 days (range 7-701). Symptomatic deep-vein thrombosis of the upper limbs developed in 48 patients (2.42%). Catheter-related infections occurred in 197 (9.96%) of the catheters inserted. They were successfully treated with antibiotics and only in 48 (2.9%) patients definitive CVC removal was required for infection and/or thrombosis or malfunctioning. CONCLUSIONS: This study represents the largest published series of consecutive patients with cancer undergoing CVC insertion under US guidance; this procedure allowed the completion of the therapeutic program for 1,930/1,978 (97.6%) of the catheters inserted. The absence of pneumotorax and other major complications indicates that US guidance should be mandatory for CVC insertion in patients with cancer.

Visualization of Fingermarks Deposits on Untreated Thermal Paper Exploiting the Near Infrared Luminescence.

Thermal paper is widely used as a print medium for different applications but it constitutes a tricky substrate for fingermark visualization. An earlier work (J Forensic Sci 2015;60:1034) reported how to visualize fingermarks on untreated thermal paper by illuminating the item with a UV-A light source. In the present paper, the potential of the near infrared (NIR) luminescence has been tested on thermal paper compared to the mentioned method. A controlled study was carried out utilizing eccrine enriched fingermarks. The promising outcomes obtained were further confirmed by performing a pseudo-operational trial. Data clearly showed that the use of the NIR filter gave better results. Finally, preliminary tests suggested a different mechanism of reaction induced by fingermarks with respect to the one behind the thermal printing. Thus, NIR luminescence represents a refinement to the suite of optical examination processes, including the potential to increase the number of marks recovered in a noncontact, nondestructive way.

Bortezomib, thalidomide, and dexamethasone followed by double autologous haematopoietic stem-cell transplantation for newly diagnosed multiple myeloma (GIMEMA-MMY-3006): long-term follow-up analysis of a randomised phase 3, open-label study.

BACKGROUND: The phase 3 GIMEMA-MMY-3006 trial, which compared bortezomib, thalidomide, and dexamethasone (VTD) combination therapy with thalidomide and dexamethasone (TD) as induction therapy before and consolidation therapy after double autologous haematopoietic stem-cell transplantation (HSCT) for newly diagnosed multiple myeloma, showed the superiority of the triplet regimen over the doublet in terms of increased complete response rate and improved progression-free survival. We report the results from the final analysis of the study. METHODS: In this randomised, open-label, phase 3 study, patients aged 18-65 years with previously untreated symptomatic multiple myeloma and a Karnofsky Performance Status of 60% or higher were enrolled at 73 centres in Italy. Patients were randomised (1:1) by a web-based system to receive three 21-day cycles of thalidomide (100 mg daily orally for the first 14 days and 200 mg daily thereafter) plus dexamethasone (total 320 mg per cycle; 40 mg on days 1-2, 4-5, 8-9, and 11-12 in the VTD regimen, and 40 mg on days 1-4 and 9-12 in the TD regimen), either alone (TD group) or with bortezomib (1·3 mg/m2 intravenously on days 1, 4, 8, and 11; VTD group). After double autologous HSCT, patients received two 35-day cycles of either the VTD or TD regimen, according to random assignment, as consolidation therapy. The primary outcome was the rate of complete response and near complete response after induction (already reported). In this updated analysis we assessed long-term progression-free survival and overall survival (secondary endpoints of the study) with an extended 10-year median follow-up, and analysed the variables influencing survival. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, NCT01134484. FINDINGS: Between May 10, 2006, and April 30, 2008, 480 patients were enrolled and randomly assigned to receive VTD (241 patients) or TD (239 patients). Six patients withdrew consent before start of treatment. 236 (99 [42%] women) in the VTD group and 238 (102 [43%] women) in the TD group were included in the intention-to-treat analysis. The data cutoff date for this analysis was May 31, 2018. Median follow-up for surviving patients was 124·1 months (IQR 117·2-131·7). The 10-year progression-free survival estimate for patients in the VTD group was 34% (95% CI 28-41) compared with 17% (13-23) for the TD group (hazard ratio [HR] 0·62 [95% CI 0·50-0·77]; p<0·0001). 60% (95% CI 54-67) of patients in the VTD group were alive at 10 years versus 46% (40-54) of patients in the TD group (HR 0·68 [95% CI 0·51-0·90]; p=0·0068). VTD was an independent predictor of improved progression-free survival (HR 0·60 [95% CI 0·48-0·76]; p<0·0001) and overall survival (HR 0·68 [0·50-0·91]; p=0·010). The incidence of second primary malignancies per 100 person-years was 0·87 (95% CI 0·49-1·44) in the VTD group compared with 1·41 (0·88-2·13) in the TD group. INTERPRETATION: Incorporation of VTD into double autologous HSCT resulted in clinically meaningful improvements in long-term progression-free survival and overall survival, confirming that a regimen including bortezomib and an immunomodulatory drug is the gold standard treatment for patients with newly diagnosed myeloma who are fit for high-dose chemotherapy. FUNDING: Seràgnoli Institute of Haematology, University of Bologna, and BolognAIL.

Oblique pelvic osteotomy in the treatment of bladder exstrophy in neonates.

Bladder exstrophy is a congenital and rare malformation of the lower abdominal wall with exposure of the bladder mucosa to the external environment, and it is related to pelvis abnormalities. Eighteen patients with bladder exstrophy were treated with bilateral oblique pelvic osteotomy in conjunction with urologic reconstruction after they were stabilized by cast. No failure of midline closure was observed (wound dehiscence or recurrence of bladder exstrophy). Follow-up showed no leg length discrepancy or problems in walking. Bilateral oblique pelvic osteotomy is a safe procedure to treat bladder exstrophy, and it results in good orthopedic and urological function.

Secondary malignancies after treatment for indolent non-Hodgkin's lymphoma: a 16-year follow-up study.

BACKGROUND: Relatively little information is available on the incidence of secondary cancer in non-Hodgkin's lymphoma. The aim of this long-term follow-up study was to determine the incidence, the time free of second tumors, and risk factors for developing secondary cancer in a homogeneous group of patients with non-Hodgkin's lymphoma. DESIGN AND METHODS: We evaluated a total of 563 patients with indolent non-Hodgkin's lymphoma enrolled in Gruppo Italiano Studio Linfomi trials from 1988 to 2003. RESULTS: After a median follow-up of 62 months, 39 patients (6.9%) developed secondary cancer: 12 myelodysplastic syndromes/acute myeloid leukemia, and 27 solid tumors. The overall standardized incidence ratio of secondary malignancy in patients with non-Hodgkin's lymphoma was higher than the risk of malignancy in the general population. The standardized incidence ratio was elevated in male patients and in patients under 65 years old at first treatment. Overall, the cumulative incidence of secondary cancer at 12 years was 10.5%, after correction in a competing-risk model. Univariate and multivariate Cox regression analyses showed that older age at the time of diagnosis, male sex, and fludarabine-containing therapy had significant negative impacts on the time free of second tumors. CONCLUSIONS: We have identified subgroups of non-Hodgkin's lymphoma patients with increased standardized incidence ratios of secondary malignancy and variables that have a negative impact on the time free of second tumors. This information could help physicians to select the most appropriate treatments. Finally, taking into account the possible occurrence of secondary neoplasia, long-term monitoring must be considered.

Prognostic relevance of serum beta2 microglobulin in patients with follicular lymphoma treated with anthracycline-containing regimens. A GISL study.

BACKGROUND AND OBJECTIVES: Although serum beta2 microglobulin (beta2 M) is an easy parameter to measure, and over-expressed in a large number of lymphoproliferative diseases, its prognostic value has been largely underestimated. The present study examined the influence of beta2M levels on overall survival (OS) of patients with follicular lymphoma (FL). DESIGN AND METHODS: The prognostic role of beta2M was evaluated in 236 patients with FL identified from the databases of the Gruppo Italiano per lo Studio dei Linfomi (GISL) and treated with anthracycline-based regimens from 1993 to 2003. RESULTS: Elevated serum beta2M levels were found in 82 patients (35%). According to multivariate logistic regression analysis, elevated beta2M levels were associated with elevated lactate dehydrogenase (LDH) (p=0.021), age (p=0.029), and number of involved nodal areas (p<0.001). The percentage of elevated beta2M levels increased progressively with increasing FLIPI scores (17%, 38%, and 63% in the low-, intermediate-, and high-risk groups, respectively). Five-year OS was 61% (95% CI, 47-73%) and 89% (95% CI, 82-93%) for patients with elevated vs normal beta2M levels respectively (p<0.001). Cox regression analysis showed that beta2M level had an independent and stable prognostic value (HR=3.0; 95%CI, 1.6-5.7). In a multivariate analysis the impact of beta2M level on survival was independent of FLIPI score, with a HR of 2.94 (95% CI, 1.54-5.62). INTERPRETATION AND CONCLUSIONS: Our results demonstrate that in patients treated in the pre-rituximabera, beta2M level was an independent prognostic marker in addition to FLIPI score. We thus suggest that beta2M be routinely assessed and tested in future prognostic studies of FL patients treated with combination chemotherapy and anti-CD20 agents.

Role of image-guided fine-needle aspiration biopsy in the management of patients with splenic metastasis.

BACKGROUND: Splenic metastases are very rare and are mostly diagnosed at the terminal phase of the disease or at the time of autopsy. The cytohistological diagnosis, when done, is made prevalently by splenectomy. Reports on splenic percutaneous biopsies in the diagnosis of splenic metastasis are fragmentary and very poor. The aims of this study are to analyse retrospectively the accuracy, safety and the clinical impact of ultrasound (US)-guided fine-needle aspiration biopsy (UG-FNAB) in patients with suspected splenic metastasis. METHODS: A retrospective analysis of 1800 percutaneous abdominal biopsies performed at our institute during the period from 1993 to 2003 was done and 160 patients that underwent splenic biopsy were found. Among these 160 patients, 12 cases with the final diagnosis of solitary splenic metastases were encountered and they form the basis of this report. The biopsies were performed under US guidance using a 22-gauge Chiba needle. All the patients underwent laboratory tests, CT examination of the abdomen and chest, US examination of abdomen and pelvis. RESULTS: There were 5 women and 7 men, median age 65 years (range 48-80). Eight patients had a known primary cancer at the time of the diagnosis of splenic metastasis: 3 had breast adenocarcinoma, 2 colon adenocarcinoma, 2 melanoma and 1 lung adenocarcinoma. Four patients were undiagnosed at the time of the appearance of splenic metastasis and subsequent investigations showed adenocarcinoma of the lung in 2 patients and colon adenocarcinoma in the remaining 2. There was a complete correspondence between the US and Computed Tomography (CT) in detecting focal lesions of the spleen. The splenic biopsies allowed a cytological diagnosis of splenic metastasis in all the 12 patients and changed clinical management in all cases. Reviewing the 160 patients that underwent UG-FNAB of the spleen we found no complications related to the biopsies. CONCLUSION: These results indicate that UG-FNAB is a successful technique for diagnosis of splenic metastasis allowing an adequate treatment of the affected patients.

Cancer diagnosis disclosure in a northern Italian hospital. Report on 312 consecutive cancer patients.

To evaluate cancer diagnosis disclosure in a cohort of cancer patients attending an outpatient oncology unit, a prospective observational study was performed. Three hundred twelve consecutive patients were accrued between January and June 2005. A questionnaire was given to each patient; the questions were very simple and related to demographics, residence, sex, educational background, employment status, time elapsed after diagnosis, treatment received, existence of relatives, and health insurance. All patients but one entered the study. There were 185 women and 127 men; 120 patients had breast cancer, 84 colorectal cancer, 34 lung cancer, 28 ovarian cancer, 34 gastric cancer, and 12 pancreatic cancer. Of the total 311 evaluable cancer patients, 171 (54.98%) were correctly informed; of the remaining 140 patients, 67 (21.54%) were not sure, and 73 (23.47%) thought their disease was not cancer. These data suggest that the majority of cancer patients attending our outpatient oncology unit are being correctly informed about their diagnosis. In our series the type of tumor had an important impact on diagnosis disclosure, while age and educational status did not.

Role of anti-hepatitis C virus (HCV) treatment in HCV-related, low-grade, B-cell, non-Hodgkin's lymphoma: a multicenter Italian experience.

PURPOSE: Hepatitis C virus (HCV) is endemic in some areas of Northwestern Europe and the United States. HCV has been shown to play a role in the development of both hepatocellular carcinoma and B-cell non-Hodgkin's lymphoma (B-NHL). The biologic mechanisms underlying the lymphomagenic activity of the virus so far are under investigation. In this study, the role of antiviral (anti-HCV) treatment in B-NHL associated with HCV infection is evaluated. PATIENTS AND METHODS: Thirteen patients with histologically proven low-grade B-NHL characterized by an indolent course (ie, doubling time no less than 1 year, no bulky disease) and carrying HCV infection were enrolled on the study. All patients underwent antiviral treatment alone with pegilated interferon and ribavirin. Response assessment took place at 6 and 12 months. RESULTS: Of the twelve assessable patients, seven (58%) achieved complete response and two (16%) partial hematologic response at 14.1 +/- 9.7 months (range, 2 to 24 months, median follow-up, 14 months), while two had stable disease with only one patient experiencing progression of disease. Hematologic responses (complete and partial, 75%) were highly significantly associated to clearance or decrease in serum HCV viral load following treatment (P = .005). Virologic response was more likely to be seen in HCV genotype 2 (P = .035), while hematologic response did not correlate with the viral genotype. Treatment-related toxicity did not cause discontinuation of therapy in all but two patients, one of whom, however, achieved complete response. CONCLUSION: This experience strongly provides a role for antiviral treatment in patients affected by HCV-related, low-grade, B-cell NHL.

Primary pancreatic lymphoma. Report of five cases.

Primary pancreatic lymphoma (PPL) is a very rare disease. We report five cases of PPL (4 men and 1 woman, mean age 65 years) diagnosed and treated at our Institution from 1987 to 1997. None of these patients had evidence of extrapancreatic disease and they were categorized as PPL involving pancreas only (stage IE, 3 patients) or pancreas and peripancreatic lymph nodes (stage IIE, 2 patients). The most common presenting symptoms were abdominal pain and weight loss. Imaging techniques showed a mass of the pancreatic head in all cases. The histological diagnosis (3 diffuse-large cell non-Hodgkin's lymphoma and 2 lymphoplasmacytic lymphoma/immunocytoma) was made by ultrasound-guided fine needle aspiration biopsy and tissue core fine-needle biopsy in three patients and by surgery in the remaining two patients. The three patients diagnosed by percutaneous biopsy were treated with chemotherapy as front-line therapy and two of them received also local radiotherapy; one of these patients is still alive in complete remission at 69 months, one died of an unrelated disease at 67 months and one died of lymphoma relapse at 88 months. Two patients underwent pancreaticoduodenectomy plus adjuvant chemotherapy; one of them died of recurrent cholangitis 8 months after surgery while the other one is still alive in complete remission after 160 months. This study shows that: 1) imaging techniques can suggest the suspicion of PPL but are unable to distinguish PPL from pancreatic adenocarcinoma; 2) histological diagnosis can be easily obtained by percutaneous US-guided tissue core biopsy; 3) surgery can be avoided both for diagnosis and therapy but the treatment of choice of PPL may only be evaluated on a larger series of patients.

[Thrombotic thrombocytopenic purpura: report of seven cases]. / Porpora trombotica trombocitopenica: descrizione di sette casi.

From May 1999 to January 2002 we observed 7 patients (4 females and 3 males, median age 55 years, range 31-81 years) with thrombotic thrombocytopenic purpura (TTP). Six patients has been previously undiagnosed and 1 patient was at second relapse. Trigger factors of TTP were identified in 6 patients: ticlopidine treatment (2 patients); an acute cutaneous infection episode immediately before the features of TTP (1 patient); presence of devices: orthodontic (1 patient) and intrauterine contraceptive (1 patient), Mycoplasma urealyticum vaginal infection (1 patient). In all the 7 patients the clinical status was mainly related to the hemolytic anemia, thrombocytopenia and neurological events. One of these patients presented with hemolytic-uremic syndrome with acute renal failure and macrohematuria at onset, another one showed a systemic exanthema post-infection-like. Six out of 7 patients presented with different neurological events: headache, confusion, focal neurological failure. All the 7 patients were promptly treated with plasma-exchange and cryosupernatant plasma infusion. In addition they received prednisone 25-50 mg/day. All the 7 patients achieved a complete remission after plasma-exchange, one relapsed 3 months later and was treated with plasma-exchange again. All the patients are in complete remission with a median follow-up of 36.3 months (range 20-62 months). From these cases we suggest: 1) clinicians should take in mind the suspicion of TTP in every patient with hemolytic, negative direct Coombs test, anemia, thrombocytopenia, high level of lactate dehydrogenase; 2) the treatment of choice is plasma-exchange; 3) the response of treatment is good if therapy is promptly and aggressively administered; 4) the possible role of a trigger factor for removing it and to prevent relapses.

Renal involvement in secondary amyloidosis of Muckle-Wells syndrome: marked improvement of renal function and reduction of proteinuria after therapy with human anti-interleukin-1ß monoclonal antibody canakinumab.

Muckle-Wells syndrome (MWS) is a rare hereditary autoinflammatory disorder characterized by recurrent urticaria-like skin rashes, arthralgias, conjunctivitis, hypoacusia, and risk of reactive AA amyloidosis due to the progressive accumulation of amyloid fibrils in different organs. Its genetic defect lies in mutations in the NLRP3 gene, encoding the cryopyrin protein, and resulting in interleukin (IL)-1ß oversecretion. Renal involvement, in terms of proteinuria or renal insufficiency, can be observed in up to 25% of patients. Herein, we describe our experience with two Caucasian patients, father and son, aged 52 and 26 years, respectively, heterozygous for both V198M and R260W NLRP3 mutations who had AA amyloid deposits on renal biopsy. The fully human monoclonal antibody canakinumab, providing selective and prolonged IL-1ß blockade, was administered in both patients every 60 days over a period of 18 months. This treatment allowed to obtain amazing results: a rapid disappearance of any clinical symptoms, the stable normalization of serum amyloid-A and, furthermore, a marked improvement of glomerular filtration rate and proteinuria with no adverse events. Our data, though limited to only two patients, emphasize that therapeutic intervention with canakinumab, suppressing both inflammation and IL-1ß-mediated manifestations, can contribute to improve kidney function in MWS with overt renal amyloidosis.