Daratumumab in multiple myeloma: experience of the multiple myeloma GIMEMA Lazio group.

Daratumumab (DARA) is a human IgG-K monoclonal antibody (MoAb) targeting CD38 that is approved alone or in combination with bortezomib and dexamethasone or lenalidomide and dexamethasone for relapsed or refractory MM (RRMM) in patients previously exposed or double refractory to proteasome inhibitors (PI) and immunomodulatory drugs (IMiDs). However, there are limited data on its clinical activity and tolerability in real-world patients. Therefore, in the present study, we aim to determine the efficacy and toxicity profile of daratumumab in a real-life setting. In this study, we report the experience of the multiple myeloma GIMEMA Lazio Group in 62 relapsed/refractory MM patients treated with daratumumab as monotherapy who had previously received at least two treatment lines including a PI and an IMiDs or had been double refractory. Patients received DARA 16 mg/kg intravenously weekly for 8 weeks, every 2 weeks for 16 weeks, and every 4 weeks until disease progression or unacceptable toxicity. The overall response rate to daratumumab was 46%. Median progression-free survival (PFS) and overall survival reached 2.7 and 22.4 months, respectively. DARA was generally well tolerated; however, 2 patients interrupted their therapy due to adverse events. Present real-life experience confirms that DARA monotherapy is an effective strategy for heavily pre-treated and refractory patients with multiple myeloma, with a favorable safety profile.

Effect of probiotic supplementation on organic feed to alternative antibiotic growth promoter on production performance and economics analysis of quail.

AIM: The purpose of this study was to know the production performance and economic analysis in quail which use probiotic supplementation to alternate antibiotic growth promoter (AGP) to feed consumption, water consumption, egg production, egg mass, feed conversion, and feed efficiency. MATERIALS AND METHODS: About 240 quails (Coturnix coturnix japonica) at 14 weeks of age were completely randomized into four treatments, each treatment consisted of six replications and each replication consisted by 10 heads. The treatment was T0 (organic feed without AGP and without probiotic), T1 (organic feed + 0.001% AGP), T2 (organic feed + 0.005% probiotic in feed), and T3 (organic feed + 0.005% probiotic in drinking water). The probiotic consist of 1.2×105 CFU/g of Lactobacillus casei and Lactobacillus rhamnosus. RESULTS: The results showed that the probiotic supplementation both in feed and water give a significant impact to feed consumption, water intake, feed conversion, feed efficiency, and quail day production, but no statistical difference of egg mass. The T3 also show the most profitable business analysis, which has the best result in income, profit, break-even point, return cost ratio, benefit-cost ratio, and return on investment. CONCLUSION: It can be concluded that giving 0.005% probiotic in drinking water to get the best egg production and profit.

Clinical and endoscopic presentation of primary gastric lymphoma: a multicentre study.

BACKGROUND: Although the stomach is the most frequent site of intestinal lymphomas, few data are available on both clinical endoscopic presentation of gastric lymphoma and possible differences between low-grade and high-grade lymphomas. METHODS: Clinical, histological and endoscopic records of consecutive patients with primary low-grade or high-grade lymphoma diagnosed were retrieved. Symptoms were categorized as 'alarm' or 'not alarm'. The endoscopic findings were classified as 'normal' or 'abnormal'. RESULTS: Overall, 144 patients with primary gastric lymphoma were detected, including 74 low-grade and 70 high-grade lymphoma. Alarm symptoms, particularly persistent vomiting and weight loss, were more frequently present in patients with high-grade lymphoma than in those with low-grade lymphoma (54% vs. 28%; P = 0.002). Low-grade lymphomas presented as 'normal' appearing mucosa (20% vs. 0%; P = 0.0004) or petechial haemorrhage in the fundus (9% vs. 0%; P = 0.02) more frequently than high-grade lymphomas, being also more often confined to the antrum (47% vs. 27%, P = 0.03) and associated with Helicobacter pylori infection (88% vs. 52%, P < 0.0001). On the contrary, high-grade lymphomas presented more commonly as ulcerative type (70% vs. 52%; P = 0.03), being also more frequently diagnosed in stage >I when compared with low-grade lymphomas (70% vs. 21%, P < 0.0001). CONCLUSIONS: The overall prevalence of alarm symptoms is quite low and may be absent in more than 70% of patients with low-grade lymphoma.

Multiple myeloma: VMCP/VBAP alternating combination chemotherapy is not superior to melphalan and prednisone even in high-risk patients.

The efficacy of alternating vincristine, melphalan (M), cyclophosphamide, prednisone/vincristine, carmustine, doxorubicin, and prednisone (VMCP/VBAP) polychemotherapy was compared with the M and prednisone (MP) regimen as induction treatment in multiple myeloma (MM). Three hundred four MM patients entered this study between March 1983 and July 1986; the analysis was performed in December 1989. The treatment groups did not show significant differences with respect to major prognostic factors. Median overall survival was 33.8 months. In the VMCP/VBAP and MP arms, after 12 induction chemotherapy cycles, 59.0% and 47.3% (P less than .068) of the patients achieved an M component reduction greater than 50%. No significant difference was observed in the two treatment arms in terms of remission duration (21.3 v 19.6 months, P less than .66) and survival (31.6 v 37.0 months, P less than .28). Patients younger than 65 years did not show any advantage from the alternating polychemotherapy. At diagnosis, the plasma cell labeling index (LI) and serum beta-2 microglobulin (beta 2-m) were evaluated in 173 and 183 patients, respectively. A significantly reduced survival was observed for patients with LI greater than or equal to 2% (16.4 months) or beta 2-m greater than or equal to 6 mg/L (20.4 months). Even in these poor-risk subgroups, VMCP/VBAP was not superior to MP.

Occurrence of a Ki-1-positive anaplastic large-cell lymphoma in a patient with Ph' positive chronic myelogenous leukemia successfully treated by alpha-interferon.

We describe a patient with Philadelphia-chromosome-positive (Ph' +) chronic myelogenous leukemia (CML), who developed an anaplastic large cell lymphoma (ALCL) with T-phenotype, after 43 months successful treatment with alpha-interferon (IFN). Characterization studies of lymphoma cells showed positivity for Ki-1 monoclonal antibody, T-cell surface markers, T-cell receptor beta chain rearrangement, and germline configuration of the BCR gene. At the time of lymphoma diagnosis, the patient had achieved complete hematologic remission from CML with partial karyotypic conversion (50% Ph' + cells). After twelve weekly courses of polychemotherapy, he obtained complete remission from lymphoma. At present, five years from CML diagnosis, the patient has a remarkably stable disease, being in remission from lymphoma and in well controlled CML chronic phase. Our case thus represents the first well documented description of a T-cell non-Hodgkin's lymphoma developed during the course of CML.

Effects of lisinopril and amlodipine on microalbuminuria and renal function in patients with hypertension.

Many patients with arterial hypertension have abnormal urinary excretion levels of albumin. This study was aimed at examining the effects of lisinopril and amlodipine on urinary excretion of albumin and kidney function. Thirty-six previously untreated patients with essential arterial hypertension were divided randomly into two groups. The first group received lisinopril 20 mg daily for 12 weeks followed by 10 mg amlodipine daily for another 12 weeks. The second group received 10 mg amlodipine daily for 12 weeks followed by 20 mg lisinopril daily for another 12 weeks. The arterial pressure decreased in a similar way with both therapies in both groups. In both groups urinary albumin excretion decreased in patients receiving lisinopril (p < 0.01). No significant changes were observed with amlodipine. This study shows that lisinopril, but not amlodipine, is able to reduce urinary excretion of albumin in patients with essential hypertension independently of its effective antihypertensive properties. It is probable that the positive effect of lisinopril on microalbuminuria is attributable to the modifications in intrarenal hemodynamics or to a change in glomerular permeability.

Forearm arterial distensibility in patients with hypertension: comparative effects of long-term ACE inhibition and beta-blocking.

Fifty patients with mild or moderate hypertension were assessed for the influence on peripheral hemodynamics of 10 months of treatment with lisinopril (25 patients) or metoprolol (25 patients). Two-dimensional Doppler flowmetry was used for the evaluation. Responding patients (blood pressure < 150/90 mm Hg) were monitored for another 4 weeks after treatment withdrawal to determine whether changes in forearm hemodynamics, if any, persisted. Twenty-two patients from either group (88%) were considered to be responders. Systolic and diastolic blood pressure in patients receiving lisinopril dropped by 6% and 15%, respectively (p < 0.001), in those receiving metoprolol the decrease was 5.9% and 14%, respectively (p < 0.001). Forearm hemodynamics was not significantly different before treatment and improved in patients receiving lisinopril, with increased compliance (p < 0.001) and lower vascular resistance (p < 0.001). No significant changes were observed with metoprolol. After withdrawal, blood pressure returned to baseline values in both groups. However, improvement in forearm hemodynamics persisted in the lisinopril group. Hemodynamics changes were statistically different on lisinopril versus metoprolol both after treatment and after withdrawal. Lisinopril, but not metoprolol, seems capable to induce regression of functional and/or structural changes of large arteries in patients with hypertension.

Effects of benazepril and nicardipine on microalbuminuria in normotensive and hypertensive patients with diabetes.

Diabetic nephropathy is the most frequent cause of chronic renal failure. The onset of microalbuminuria in patients with diabetes mellitus, which seems to be related to blood pressure and the control of glycemia, is predictive of the development of true proteinuria. This multicenter, single-blind, randomized study examined the effects of benazepril and nicardipine on overnight microalbuminuria in 57 normotensive and 46 hypertensive diabetic patients. At the end of a 3-month placebo run-in period, the patients were stratified on the basis of the presence or absence of arterial hypertension and, within each stratum, randomized to receive one daily tablet of 10 mg benazepril or one tablet of 20 mg nicardipine twice daily for 6 months. Renal hemodynamics was investigated in 25 patients. Both drugs decreased overnight microalbuminuria throughout the study period, but benazepril was more effective than nicardipine (p = 0.025); in the patients with hypertension, both drugs led to a similar marked reduction in systolic and diastolic blood pressure. This study shows that benazepril was more effective than nicardipine in reducing overnight microalbuminuria in patients with diabetes mellitus, independently of their antihypertensive properties.

Large artery compliance in essential hypertension. Effects of calcium antagonism and beta-blocking.

This study used 2D Doppler flowmetry to assess the effects on peripheral hemodynamics of effective treatment with nicardipine or atenolol in 40 patients with mild or moderate essential hypertension. Two groups of 20 patients received treatment with nicardipine or atenolol, respectively, for 8 months. Consequently, those patients considered to be responders (blood pressure less than 150/90 mm Hg) were monitored for another 4 weeks after the therapy was suspended in order to determine whether the changes, if any, in arterial compliance persisted. Following the 8-month therapy, four patients from each group were excluded from the study because of unsatisfactory blood pressure levels. After the treatment, there was a decrease in blood pressure in both groups (P less than .01). In the nicardipine group, there was a significant increase in diameter and compliance (P less than .01), whereas pulse wave velocity and resistance decreased (P less than .01). In the atenolol group, these parameters did not change significantly. After therapy was ended, blood pressure returned to baseline values in both groups. However, in the nicardipine group, the observed improvement in forearm hemodynamics persisted. This result may indicate that nicardipine is able to induce a regression of functional and/or structural changes in the large arteries of hypertensive patients.

A phase II trial on alpha-interferon (alpha IFN) effect in patients with monoclonal IgM gammopathy.

Waldenström's macroglobulinemia (WM) is an incurable disorder of B cells. Following occasional reports of response to alpha interferon (IFN) and in view of its effectiveness in hairy cell leukemia, we tested this agent in a relatively large group (n = 88) of patients who had an IgM monoclonal component (MC) greater than 10 g/l. Thirty eight patients had a MC > 30 g/l and were classified as Waldenström's macroglobulinemia (WM), while fifty had either WM in an early stage or an IgM monoclonal gammopathy of undeterminated significance (all of them operationally classified as IgM-MGUS). All patients received IFN 3 MU/day for one month and then 3 times/week. Response to treatment was mainly based on MC reduction in two consecutive determinations (> 50%: major response; 25-50%: minor response). Of 36 evaluable WM patients, 12 had a major and 6 a minor response; of 41 evaluable IgM-MGUS patients, 2 had a major and 6 a minor response. In WM patients with a major response, MC reduction was associated with disappearance of hyperviscosity symptoms, raised Hb level and reduced bone marrow lymphoplasmacytosis. At the dose used, tolerance was excellent in the majority of patients; only 15% withdrew from the study due to side effects. Although single cases and very small series have already been reported, no large study collecting quantitative data on the effects of alpha IFN in WM has been published so far. Our results suggest that IFN treatment is not indicated for patients with a low monoclonal component, while it is of clinical benefit in about 50% of patients with IgM > 30 g/l.

Comparison of the effects of nicardipine and metoprolol on lipid and glycidic metabolism in hypertensive subjects.

Various aspects of carbohydrate and lipid metabolism have been studied in two groups of patients with mild hypertension before and after six months of treatment with either nicardipine (n = 10) or metoprolol (n = 10). A significant reduction of the arterial blood pressure was seen with both treatment regimens. Circulating plasma glucose, insulin, C peptide and triglyceride concentrations were measured at hourly intervals from 08 h 00 to 17 h 00, in patients on an isocaloric diet (35 kcalth/kg/die). Plasma glucose concentrations were unchanged and insulin and C peptide concentrations were higher in association with metoprolol treatment. In contrast, nicardipine-treated patients had similar plasma insulin, but lower plasma glucose, C peptide and triglyceride concentrations after treatment. The changes in day-long plasma glucose and insulin-stimulated glucose uptake had increased in association with metoprolol treatment and decreased following nicardipine. Finally plasma cholesterol concentrations did not change following metoprolol therapy, whereas plasma high density lipoprotein cholesterol increased in association with nicardipine treatment. The data seem to indicate that the negative effect of nicardipine on secretion of insulin is balanced by an improvement in glucose uptake.

Acute non lymphoid leukemia following CMF treatment as adjuvant therapy in positive node breast cancer. Case report.

The CMF regimen as an adjuvant therapy for breast cancer with axillary node involvement has become "standard therapy" at least for some subsets of patients (according to the Second Consensus Development Conference on Adjuvant Chemotherapy for Breast Cancer). The acute toxicity of such a regimen is usually mild and well tolerated; the late toxicity is mainly represented by amenorrhea. Here a case of acute non-lymphoid-leukemia (ANLL) after six CMF cycles is reported.

[A comparative study of the effects of lisinopril and quinapril administered once a day in essential hypertension]. / Studio comparativo degli effetti del lisinopril e del quinapril in monosomministrazione giornaliera nell'ipertensione essenziale.

The aim of the study was to compare efficacy and safety of quinapril and lisinopril once-daily administered in patients with mild to moderate hypertension. After a two-week placebo period, 23 patients with sitting diastolic blood pressure between 95 and 110 mmHg were randomly assigned to the therapy with quinapril 20 mg/die or lisinopril 10 mg/die for 4 weeks in a single-blind design. After 4 weeks patients with diastolic blood pressure greater than 90 mmHg were treated with a higher dose (lisinopril 20 mg/die; quinapril 40 mg/die). Therapy with lisinopril normalized 83% of patients, and quinapril 45% of patients. Lisinopril was significantly better than quinapril in reducing blood pressure after 4 and 8 weeks of active treatment. The 24 hours ambulatory blood pressure monitoring showed that quinapril failed to control blood pressure after 12 hours from the administration of the drug.

[Antihypertensive action of nicardipine retard in 24 hours and its effect on stress]. / Azione antiipertensiva della Nicardipina Retard nelle 24 ore e suo comportamento nello stress.

Thirty-six patients (17 males and 19 females), aged between 40 and 70 years old (mean age 55.9), suffering from slight or moderate arterial hypertension, were monitored for four weeks after 14 days of placebo treatment. In a double-blind and random study 24 patients were treated with Nicardipine Retard (40 mg twice a day) whereas a further 12 received placebo twice a day. Sphigomanometric controls carried out after two and four weeks showed a significant reduction in arterial pressure only in those patients receiving active treatment. 24-hour out-patient monitoring of arterial pressure, carried out using Spacelabs 5300, showed a reduction in both systolic and diastolic arterial pressure throughout the day in subjects treated with calcium-antagonists compared to the placebo group. The normal physiological 24-hour trend of arterial pressure was always taken into account. The pressure response to a cold pressor test, mental arithmetic test, isometric and dynamic effort tests, measuring using a cycloergometer, was not modified by anti-hypertensive treatment, thus confirming the preservation of normal physiological behaviour during daily activities. There was no significant change in heart rate and the drug was well tolerated.

[Clinico-hematological evaluation of 57 patients undergoing antiaggregant treatment with indobufen]. / Valutazione clinico-ematologica di 57 pazienti in trattamento antiaggregante con indobufene.

A long-term administration of Indobufen, 400 mg daily, was evaluated in 57 patients with cardiovascular diseases. Aggregation waves induced by ADP, collagen and epinephrine showed a significant and persistent inhibition of platelet function. Minor side effects were observed and in 6 patients the drug was withdrawn: 4 patients began to experience gastric troubles, 1 patient had positive occult test for blood, 1 patient developed an allergic rush. Clinical evaluation and platelet aggregation study before starting indobufen and during the follow up period seem to be useful in the evaluation of effectiveness, safety, compliance and suitable daily dose.

Efficacy of lenalidomide in association with cyclophosphamide and dexamethasone in multiple myeloma patient with bilateral retro-orbital localisation.

Extramedullary localisation is an uncommon manifestation in multiple myeloma (MM). Ocular involvement is rare. Here, we describe a relapse of MM with bilateral retro-orbital localisation without any bone involvement with good and rapid response to therapy with lenalidomide, dexamethasone, and cyclophosphamide.

Efficacy and tolerability of bendamustine, bortezomib and dexamethasone in patients with relapsed-refractory multiple myeloma: a phase II study.

Bendamustine demonstrated synergistic efficacy with bortezomib against multiple myeloma (MM) cells in vitro and seems an effective treatment for relapsed-refractory MM (rrMM). This phase II study evaluated bendamustine plus bortezomib and dexamethasone (BVD) administered over six 28-day cycles and then every 56 days for six further cycles in patients with rrMM treated with 4 prior therapies and not refractory to bortezomib. The primary study end point was the overall response rate after four cycles. In total, 75 patients were enrolled, of median age 68 years. All patients had received targeted agents, 83% had 1-2 prior therapies and 33% were refractory to the last treatment. The response ratepartial response (PR) was 71.5% (16% complete response, 18.5% very good PR, 37% partial remission). At 12 months of follow-up, median time-to-progression (TTP) was 16.5 months and 1-year overall survival was 78%. According to Cox regression analysis, only prior therapy with bortezomib plus lenalidomide significantly reduced TTP (9 vs 17 months; hazard ratio=4.5; P=0.005). The main severe side effects were thrombocytopenia (30.5%), neutropenia (18.5%), infections (12%), neuropathy (8%) and gastrointestinal and cardiovascular events (both 6.5%). The BVD regimen is feasible, effective and well-tolerated in difficult-to-treat patients with rrMM.

Evolution of bisphosphonate-related osteonecrosis of the jaw in patients with multiple myeloma and Waldenstrom's macroglobulinemia: a retrospective multicentric study.

Bisphosphonates (BPs) are used intravenously to treat cancer-related conditions for the prevention of pathological fractures. Osteonecrosis of the jaw (BRONJ) is a rare complication reported in 4-15% of patients. We studied, retrospectively, 55 patients with multiple myeloma or Waldenstrom's macroglobulinemia followed up from different haematological departments who developed BRONJ. All patients were treated with BPs for bone lesions and/or fractures. The most common trigger for BRONJ was dental alveolar surgery. After a median observation of 26 months, no death caused by BRONJ complication was reported. In all, 51 patients were treated with antibiotic therapy, and in 6 patients, this was performed in association with surgical debridement of necrotic bone, in 16 with hyperbaric O(2) therapy/ozonotherapy and curettage and in 12 with sequestrectomy and O(2)/hyperbaric therapy. Complete response was observed in 20 cases, partial response in 21, unchanged in 9 and worsening in 3. The association of surgical treatment with antibiotic therapy seems to be more effective in eradicating the necrotic bone than antibiotic treatment alone. O(2) hyperbaric/ozonotherapy is a very effective treatment. The cumulative dosage of BPs is important for the evolution of BRONJ. Because the most common trigger for BRONJ was dental extractions, all patients, before BP treatment, must achieve an optimal periodontal health.