Radioimmunotherapy versus autologous hematopoietic stem cell transplantation in relapsed/refractory follicular lymphoma: a Fondazione Italiana Linfomi multicenter, randomized, phase III trial.

BACKGROUND: Optimal consolidation for young patilents with relapsed/refractory (R/R) follicular lymphoma (FL) remains uncertain in the rituximab era, with an unclear benefit of autologous stem cell transplantation (ASCT). The multicenter, randomized, phase III FLAZ12 (NCT01827605) trial compared anti-CD20 radioimmunotherapy (RIT) with ASCT as consolidation after chemoimmunotherapy, both followed by rituximab maintenance. PATIENTS AND METHODS: Patients (age 18-65 years) with R/R FL and without significant comorbidities were enrolled and treated with three courses of conventional, investigator-chosen chemoimmunotherapies. Those experiencing at least a partial response were randomized 1 : 1 to ASCT or RIT before CD34+ collection, and all received postconsolidation rituximab maintenance. Progression-free survival (PFS) was the primary endpoint. The target sample size was 210 (105/group). RESULTS: Between August 2012 and September 2019, of 164 screened patients, 159 were enrolled [median age 57 (interquartile range 49-62) years, 55% male, 57% stage IV, 20% bulky disease]. The study was closed prematurely because of low accrual. Data were analyzed on 8 June 2023, on an intention-to-treat basis, with a 77-month median follow-up from enrollment. Of the 141 patients (89%), 70 were randomized to ASCT and 71 to RIT. The estimated 3-year PFS in both groups was 62% (hazard ratio 1.11, 95% confidence interval 0.69-1.80, P = 0.6662). The 3-year overall survival also was similar between the two groups. Rates of grade ≥3 hematological toxicity were 94% with ASCT versus 46% with RIT (P < 0.001), and grade ≥3 neutropenia occurred in 94% versus 41%, respectively (P < 0.001). Second cancers occurred in nine patients after ASCT and three after radioimmunotherapy (P = 0.189). CONCLUSIONS: Even if prematurely discontinued, our study did not demonstrate the superiority of ASCT versus RIT. ASCT was more toxic and demanding for patients and health services. Both strategies yielded similar, favorable long-term outcomes, suggesting that consolidation programs milder than ASCT require further investigation in R/R FL.

Production and persistence of specific antibodies in COVID-19 patients with hematologic malignancies: role of rituximab.

The ability of patients with hematologic malignancies (HM) to develop an effective humoral immune response after COVID-19 is unknown. A prospective study was performed to monitor the immune response to SARS-CoV-2 of patients with follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), chronic lymphoproliferative disorders (CLD), multiple myeloma (MM), or myelodysplastic/myeloproliferative syndromes (MDS/MPN). Antibody (Ab) levels to the SARS-CoV-2 nucleocapsid (N) and spike (S) protein were measured at +1, +3, +6 months after nasal swabs became PCR-negative. Forty-five patients (9 FL, 8 DLBCL, 8 CLD, 10 MM, 10 MDS/MPS) and 18 controls were studied. Mean anti-N and anti-S-Ab levels were similar between HM patients and controls, and shared the same behavior, with anti-N Ab levels declining at +6 months and anti-S-Ab remaining stable. Seroconversion rates were lower in HM patients than in controls. In lymphoma patients mean Ab levels and seroconversion rates were lower than in other HM patients, primarily because all nine patients who had received rituximab within 6 months before COVID-19 failed to produce anti-N and anti-S-Ab. Only one patient requiring hematological treatment after COVID-19 lost seropositivity after 6 months. No reinfections were observed. These results may inform vaccination policies and clinical management of HM patients.

Eculizumab treatment in patients with COVID-19: preliminary results from real life ASL Napoli 2 Nord experience.

OBJECTIVE: SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2)-related pneumonia, referred to as COVID-19 (Coronavirus Disease 19), is a public health emergency as it carries high morbidity, mortality, and has no approved specific pharmacological treatments. In this case series, we aimed to report preliminary data obtained with anti-complement C5 therapy with eculizumab in COVID-19 patients admitted to intensive care unit (ICU) of ASL Napoli 2 Nord. PATIENTS AND METHODS: This is a case series of patients with a confirmed diagnosis of SARS-CoV2 infection and severe pneumonia or ARDS who were treated with up to 4 infusions of eculizumab as an off-label agent. Patients were also treated with anticoagulant therapy with Enoxaparin 4000 IU/day via subcutaneous injection, antiviral therapy with Lopinavir 800 mg/day + Ritonavir 200 mg/day, hydroxychloroquine 400 mg/day, ceftriaxone 2 g/day IV, vitamine C 6 g/day for 4 days, and were on Non-Invasive Ventilation (NIV). RESULTS: We treated four COVID-19 patients admitted to the intensive care unit because of severe pneumonia or ARDS. All patients successfully recovered after treatment with eculizumab. Eculizumab induced a drop in inflammatory markers. Mean C Reactive Protein levels dropped from 14.6 mg/dl to 3.5 mg/dl and the mean duration of the disease was 12.8 days. CONCLUSIONS: Eculizumab has the potential to be a key player in treatment of severe cases of COVID-19. Our results support eculizumab use as an off-label treatment of COVID-19, pending confirmation from the ongoing SOLID-C19 trial.

Lenalidomide plus R-CHOP21 in newly diagnosed diffuse large B-cell lymphoma (DLBCL): long-term follow-up results from a combined analysis from two phase 2 trials.

Lenalidomide-RCHOP (R2-CHOP21) has been shown to be safe and effective in patients with untreated diffuse large B-cell lymphoma (DLBCL). The aim of this analysis is to report long-term outcome and toxicities in newly diagnosed DLBCL patients who received R2-CHOP21 in two independent phase 2 trials, conducted by Mayo Clinic (MC) and Fondazione Italiana Linfomi (FIL). All patients received R-CHOP21 plus lenalidomide. Long-term progression-free survival (PFS), time to progression (TTP), overall survival (OS) and late toxicities and second tumors were analyzed. Hundred and twelve patients (63 MC, 49 FIL) were included. Median age was 69 years, 88% were stage III-IV. At a median follow-up of 5.1 years, 5y-PFS was 63.5%, 5y-TTP 70.1% and 5y-OS 75.4%; according to cell of origin (COO): 5y-PFS 52.8% vs 64.5%, 5y-TTP 61.6% vs 69.6% and 5y-OS 68.6% vs 74.1% in germinal center (GCB) vs non-GCB respectively. Four patients experienced grade 4-5 late toxicities. Grade ≤ 3 toxicities were infections (N = 4), thrombosis (N = 1) and neuropathy (N = 3). Seven seconds tumors were observed. Long-term follow-up demonstrates that R2-CHOP21 efficacy was maintained with high rates of PFS, TTP, and OS. Lenalidomide appears to mitigate the negative prognosis of non-GCB phenotype. Incidence of therapy-related secondary malignancies and late toxicities were low.

Value of real-time gastric juice analysis in upper gastrointestinal endoscopy.

AIM: Esophagogastroduodenoscopy (EGDS) cannot identify microscopic lesions. We determined the contribution of real-time gastric juice analysis in detecting lesions non-detectable with the simple endoscopic inspection. METHODS: Endoscopy, histology and gastric juice analysis were performed in 216 patients. We assessed six diagnostic strategies: EGDS (strategy-1), EGDS with antral biopsies (hematoxylin-eosin staining) in hypochlorhydrics (strategy-2) or all patients (strategy-3), EGDS with antral and fundic biopsies (hematoxylin-eosin staining) in hypochlorhydrics (strategy-4) or all patients (strategy-5), EGDS with antral and fundic biopsies (hematoxylin-eosin + immunohistochemical staining) in hypochlorhydrics (strategy-6). Then, we determined how many of the pathological conditions identified by the complete histological evaluation would have been detected by each strategy. RESULTS: In total, 220 pathological conditions were identified. Hypochlorhydria was correlated (r=0.67; P<0.01) with histological lesions (85% lesions were detected in hypochlorhydrics) and high ammonium levels, with H.pylori infection (r=0.69; P<0.01). Strategy-1 identified only 5% conditions, while strategies 3 and 5 detected 68.6% and 83.2% conditions, respectively. Strategies 2, 4 and 6 (based on gastric juice analysis) yielded detection rates (61.4%, 75.5%, 90.9%) similar to or better than those of strategies 3 and 5. CONCLUSION: Real-time gastric juice analysis provided information about the presence of gastric lesions in an otherwise "normal" stomach at EGDS. It improved the diagnostic yield and optimized resource utilization without any additional effort by the endoscopist.

Antiviral treatment in patients with indolent B-cell lymphomas associated with HCV infection: a study of the Fondazione Italiana Linfomi.

BACKGROUND: Tumor regression after antiviral therapy (AT) is in favor of an etiological role of hepatitis C virus (HCV) in non-Hodgkin's B-cell lymphomas (NHL). PATIENTS AND METHODS: We carried out a cohort study of 704 consecutive HIV-negative, HCV-positive patients with indolent NHL diagnosed and treated from 1993 to 2009 in 39 centers of the Fondazione Italiana Linfomi; 134 patients were managed with AT for lymphoma control. RESULTS: For entire cohort, 5-year overall survival (OS) was 78% [95% confidence interval (CI): 74%-82%] and 5-year progression-free survival (PFS) was 48% (95% CI: 44%-53%). In multivariate analysis, the use of AT during the patients' life had positive impact on OS. Forty-four of the 100 patients treated with first-line AT achieved a complete remission (CR) and 33 a partial response (PR). HCV-RNA clearance was achieved in 80 patients and was related to lymphoma response. At a median follow-up of 3.6 years, 5-year PFS was 63% (95% CI: 50%-73%). CR + PR rate was 85% with AT as second-line treatment. CONCLUSION: AT produces HCV-RNA clearance and consequent tumor regression in most patients with HCV-related indolent NHL. AT used at any time is associated with improved OS. Consequently, AT can be considered an option for patients with indolent lymphomas who do not need immediate cytoreductive treatment.

Preference for involvement in treatment decisions and request for prognostic information in newly diagnosed patients with higher-risk myelodysplastic syndromes.

BACKGROUND: The main objective of this study was to assess preferences for involvement in treatment decisions and requests for prognostic information in newly diagnosed higher-risk myelodysplastic syndrome (MDS) patients. PATIENT AND METHODS: This was a prospective cohort observational study that consecutively enrolled MDS patients with an international prognostic scoring system (IPSS) risk category of intermediate-2 or high risk (summarized as 'higher risk'). The control preference scale was used to assess patient preferences for involvement in treatment decisions, and whether a request by patients for prognostic information during consultation was made, was also recorded. All of the patients were surveyed at the time of diagnosis before receiving treatment. Univariate and multivariate analyses were carried out to assess how sociodemographic, clinical and laboratory data related to decision-making preferences and requests for prognostic information. Relationship with the health-related quality of life (HRQOL) profile was also examined. RESULTS: A total of 280 patients were enrolled, 74% with intermediate-2 and 26% with high-risk IPSS. The mean age of patients was 70-year old (range: 32-89 years). One hundred thirty-two patients (47%) favored a passive role in treatment decision-making, whereas only 14% favored an active role. The remaining 39% of patients favored a shared decision-making approach. Patients with lower hemoglobin levels were more likely to prefer a passive role (P=0.037). HRQOL was generally better in patients preferring an active role versus those preferring a passive one. Overall, 61% (N=171) of patients requested prognostic information on survival during consultation. The likelihood of not requesting prognostic information was higher for older patients (P = 0.003) and for those with lower education (P=0.010). CONCLUSION: Decision-making preferences vary among patients with newly diagnosed higher-risk MDS. Current findings suggest that patients with worse underlying health conditions are more likely to prefer less involvement in treatment decisions.

Perendoscopic real-time assessment of pH improves detection of gastric preneoplastic conditions.

AIM: Gastric juice may constitute a precious source of clinicopathological information. We assessed the usefulness of real-time, perendoscopic, gastric juice pH determination in identifying preneoplastic conditions of the stomach, that often escape the mere endoscopic evaluation. METHODS: The study included 245 patients (115M; 130F; age 47±17). In each of them perendoscopic gastric juice pH was assessed by means of an innovative device, the Endofaster, and the results were correlated with histological evaluation (H&E, immunohistochemistry, argyrophil stains), and gastric acid secretion (BAO-PAO), and serum gastrin levels. The conditions evaluated were: atrophy, intestinal metaplasia, endocrine cell hyperplasia, hypergastrinemia. RESULTS: A total of 136 pathological conditions were detected and these resulted to be correlated with pH (r=0.67; P<0.01). The rate of pathological conditions was low in normochlorhydric patients (14.1%); most of these conditions were concentrated in patients with hypochlorhydria (85.9%) (P<0.001). Specifically, the number of patients with one or more pathological conditions increased proportionately with the rise in pH levels. An inverse correlation was detected between gastric juice pH and basal acid output (BAO) (r=-0.72; P<0.01). Endoscopic feature was normal/mild in most of patients with pathological conditions. CONCLUSION: Hypochlorhydria is a sensitive indicator of gastric risk conditions. Perendoscopic real-time assessment of pH can improve and extend optical analysis by allowing the detection of pathological conditions (either preneoplastic or not) that often escape diagnosis because not correlated with specific endoscopic pattern.

Clinical and molecular characterization of diffuse large B-cell lymphomas with 13q14.3 deletion.

BACKGROUND: Deletions at 13q14.3 are common in chronic lymphocytic leukemia and are also present in diffuse large B-cell lymphomas (DLBCL) but never in immunodeficiency-related DLBCL. To characterize DLBCL with 13q14.3 deletions, we combined genome-wide DNA profiling, gene expression and clinical data in a large DLBCL series treated with rituximab, cyclophosphamide, doxorubicine, vincristine and prednisone repeated every 21 days (R-CHOP21). PATIENTS AND METHODS: Affymetrix GeneChip Human Mapping 250K NspI and U133 plus 2.0 gene were used. MicroRNA (miRNA) expression was studied were by real-time PCR. Median follow-up of patients was 4.9 years. RESULTS: Deletions at 13q14.3, comprising DLEU2/MIR15A/MIR16, occurred in 22/166 (13%) cases. The deletion was wider, including also RB1, in 19/22 cases. Samples with del(13q14.3) had concomitant specific aberrations. No reduced MIR15A/MIR16 expression was observed, but 172 transcripts were significantly differential expressed. Among the deregulated genes, there were RB1 and FAS, both commonly deleted at genomic level. No differences in outcome were observed in patients treated with R-CHOP21. CONCLUSIONS: Cases with 13q14.3 deletions appear as group of DLBCL characterized by common genetic and biologic features. Deletions at 13q14.3 might contribute to DLBCL pathogenesis by two mechanisms: deregulating the cell cycle control mainly due RB1 loss and contributing to immune escape, due to FAS down-regulation.

Optimizing clinical care in patients with advanced soft tissue sarcoma: a phase II study of a new schedule of high-dose continuous infusion ifosfamide and doxorubicin combination.

BACKGROUND: Ifosfamide and doxorubicin combination is an active regimen for patients with advanced soft tissue sarcomas (STS) but is burdened by high toxicity. A phase II trial was designed to assess the activity of continuous infusion ifosfamide and doxorubicin combination. PATIENTS AND METHODS: Thirty-four chemotherapy-naive patients with advanced STS were treated with ifosfamide (13 g/m(2)/12 days as continuous infusion) and doxorubicin (75 mg/m(2) on day 8) every 28 days with granulocyte colony-stimulating factor. RESULTS: The major toxicity was hematological: grade 3/4 neutropenia, anemia and thrombocytopenia occurred in 63, 30 and 12% of patients, respectively. The disease control rate was 68% and the median time to progression was 7.1 months. Among leiomyosarcomas, 2 partial responses and 4 stable diseases were observed. CONCLUSIONS: Our study confirms that the ifosfamide and doxorubicin combination has a very low non-hematological toxicity profile. This regimen attained a high disease control rate with moderate activity. Further investigation into leiomyosarcoma is warranted.

2-Chloroadenosine and human prostate cancer cells.

Cladribine, i.e.2-deoxy-Chloroadenosine is currently in use as chemotherapeutic agent in chronic lymphoid malignancies and pediatric acute myelogenous leukemia whereas the structurally related counterpart, 2-Chloroadenosine, has been less studied. Nevertheless, 2-Chloroadenosine has been shown to be capable of inducing apoptosis in several cell lines by acting either via adenosine receptors or via uptake that is followed by metabolic transformations leading to nucleotide analogues, i.e. antimetabolites effective in the treatment of a variety of malignancies. Triphosphate nucleoside analogues show specificity for cell in S-phase, inhibit DNA synthesis and kill the cells by mechanisms still largely unknown. 2-Chloroadenosine, at low micromolar concentration, acts as a metabolic precursor of an S-phase specific nucleoside analogue in human prostate cancer PC3 cells and inhibits DNA synthesis thereby leading to accumulation of cells in the S-phase. However, although responsible for the acquisition of resistance, the adenosine derivative is capable of sensitising the cells to the action of other antineoplastic agents and the ability of nucleoside analogues to trigger cell cycle arrest can be exploited to maximize cytotoxicity in combination with cell cycle checkpoint disregulators. 2-Chloroadenosine, in combination with Docetaxel, known to improve the survival of hormone-refractory prostate cancer patients, further decreases in vitro PC3 cell proliferation and invasiveness. Moreover, 2-Chloroadenosine is capable of modulating PAR-1 and IL-23 gene expression suggesting a modulation of cancer metastasis and immune system activity. The present review summarizes research performed in our laboratory to propose a novel role for 2-Chloroadenosine as an anticancer agent.

Immunochemotherapy with in vivo purging and autotransplant induces long clinical and molecular remission in advanced relapsed and refractory follicular lymphoma.

BACKGROUND: To evaluate the clinical outcome of patients with relapsed or refractory follicular lymphoma treated with immunochemotherapy, in vivo purging and high-dose therapy with autotransplant. PATIENTS AND METHODS: Sixty-four patients were enrolled in the trial. Primary end point was progression-free survival (PFS). Secondary end points were the in vivo purging effect on stem-cell harvest and the impact of molecular response on the outcome. RESULTS: At enrollment, 59% of patients were PCR+ for bcl-2 rearrangement in bone marrow (PCR-informative). After the immunochemotherapy, before mobilization, 97% obtained complete response or partial response and 87% of patients informative for bcl-2 were molecularly negative. Sixty-one patients proceeded to in vivo purging and peripheral blood stem cell (PBSC) mobilization with rituximab and high-dose AraC. The median number of CD34+ cells collected was 16.6 x 10(6)/kg. Of 33 PCR-informative patients, the harvests resulted in PCR- in all. Fifty-eight patients received high-dose therapy and autotransplant of in vivo purged PBSC. After a median follow-up of 3.5 years, 41 patients are in complete remission. Five-year PFS is 59%. CONCLUSION: This study demonstrates that patients with advanced relapsed or refractory follicular lymphoma treated with immunochemotherapy, in vivo purging and autotransplant may obtain long-lasting PFS. In bcl-2-positive patients, in vivo purging allows the harvest of lymphoma-free PBSC. Absence of the bcl-2 rearrangement after autotransplant is associated with persistent clinical remission.

Late computed tomography scan response improvement and gallium scintigraphy evaluation as on-treatment prognostic parameters to tailor treatment intensity in patients with Hodgkin's lymphoma. A prospective phase II study.

BACKGROUND: Tailoring treatment intensity is critical in Hodgkin's lymphoma (HL). Ongoing prognostic parameters may be an useful adjunct to pretreatment stratification. We used the kinetics of computed tomography (CT) scan response and residual gallium (Ga)-67 uptake to better stratify risk. MATERIALS AND METHODS: Patients received 4-8 adriamycin, bleomycin, vinblastine and dacarbazine courses according to stage. Disease was reassessed evaluating late computed tomography scan response improvement (CTRI) and Ga-67 uptake. Patients received no further treatment, radiotherapy (RT) or additional chemotherapy + RT according to the presence of none (low risk), one (intermediate risk) and both parameters (high risk). Patients with bulky mediastinum received RT anyhow. RESULTS: Among 102 assessable patients, 35 showed late CTRI and 9 residual Ga-67 uptake. In 30 patients with bulky mediastinum, the 3-year progression-free survival (PFS) was significantly better when neither parameter was present (100% versus 69%; P = 0.02). In 72 patients without bulky mediastinum, treatment was tailored according to risk assignment. Relapses occurred in 5 of 47 low-risk and 3 of 21 intermediate-risk patients, with no differences between the two groups, and in 3 of 4 high-risk patients. CONCLUSION: This study shows that two on-treatment parameters, late CTRI and residual Ga-67 uptake, can predict PFS in HL and identify patients in which RT can be spared without apparently affecting the outcome.

Mapping the intake of different elements in vegetal tissues by dual-energy X-ray imaging at DaPhine synchrotron light source.

This article reports on the first utilization of the soft X-ray beamline at the DaPhine synchrotron light source for mapping the intake of different elements in plant tissues. As a test, the method of dual-energy X-ray microradiography was applied to the investigation of the natural sulfur content in dried leaf and root samples. Our ultimate goal was to monitor the pollutant lead and its intake, which was added in controlled doses to the hydroponic medium of laboratory-controlled samples of vegetal species. The results obtained by the nondestructive X-ray radiographic analysis are compared to the values of concentrations determined by a standard chemical analysis utilizing atomic absorption spectroscopy. From this comparison the validity of the X-ray detection of heavy metals in biological samples has been confirmed. The superposition of the dual energy results on the simple planar radiography shows the representation of the pollutant intake directly on the sample structures. It should be pointed out that this method, developed here for plant root and leaves could be applied to any biological sample of interest, but the preparation and observation conditions necessitate different strategies according to the type of sample under analysis.

Monitoring of the heavy-metal hyperaccumulation in vegetal tissues by X-ray radiography and by femto-second laser induced breakdown spectroscopy.

This article reports on the utilization of X-ray microradiography and laser induced breakdown spectroscopy (LIBS) techniques for investigation of the metal accumulation in different part of leaf samples. The potential of the LIBS-analysis for finding the proper plant species for phytoremediation is compared with the results of microradiography measurements at the HERCULES source at ENEA, Rome (Italy) and X-ray microradiography experiments at the ELETTRA Synchrotron, Trieste (Italy).

[Growth curves in pediatrics. Pilot study in a city of south of Italy]. / Valori di crescita in soggetti pediatrici.

AIM: In the past years the body composition assessment in pediatric subjects showed great changes due to the different quality of life and different diet habits. Over-weight and obesity increased tremendously not only in the industrialized societies but also in developing countries. Growth curves developed in the 60s need to be revises in the light of these changes and population specific curves are needed to follow a population with different life style and energy intake. The aim of this study was to evaluate, in a city of South Italy (San Severo), pediatric subjects in order to create growth curves. METHODS: Between May 1999 and October 2000 we evaluated 2,262 subjects: 1,172 (51.8%) males and 1,090 (48.2%) females, age range 6-11 years (mean 8.48 +/- 2.28 years). Height, weight, thoracic circumference and body mass index (BMI) were measured by the same expert operator. RESULTS: Tables and figures for weight, height, thoracic circumferences and BMI at 3 degrees, 50 degrees, 97 degrees centile for age and gender were presented. A comparison between 50 degrees centile for BMI in males and females were also done showing the different development related to gender. CONCLUSIONS: The results obtained underline the importance of an auxologic follow-up of the pediatric subjects in order to evaluate their correct development. The specific growth curves available make it possible to analyze the development of subjects in comparison with the subjects studied for the curves development. Moreover, the importance of the BMI curve and the relationship of the 50 degrees centile in males and females showing the different growth curve related to gender, is underlined.