Standardisation of minimal residual disease in multiple myeloma.

The assessment of the effectiveness of chemotherapy in oncology cannot disregard the concept of minimal residual disease (MRD). In fact, the efforts of numerous scientific groups all over the world are currently focusing on this issue, with the sole purpose of defining sensitive, effective assessment criteria that are, above all, able to give acceptable, easily repeatable results worldwide. Regarding this issue, especially with the advent of new drugs, multiple myeloma is one of the haematologic malignancies for which a consensus has not yet been reached. In this review, we analyse various techniques that have been used to improve the sensitivity of response, aimed at reducing the cut-off values previously allowed, as well as serological values like serum-free light chain, or immunophenotypic tools on bone marrow or peripheral blood, like multi-parameter flow cytometry, or molecular ones such as allele-specific oligonucleotide (ASO)-qPCR and next-generation/high-throughput sequencing technologies (NGS). Moreover, our discussion makes a brief reference to promising techniques, such as mass spectrometry for identifying Ig light chain (LC) in peripheral blood, and the assessment of gene expression profile not only in defining prognostic risk at the diagnosis but also as a tool for evaluation of response.

Cutaneous adverse reactions to lenalidomide.

Lenalidomide is an immunomodulatory drug (IMiD) used principally in the treatment of multiple myeloma (MM), myelodysplastic syndromes (MS) and amyloidosis. Adverse reactions related to lenalidomide include myelosuppression (mainly neutropenia but also thrombocytopenia), gastrointestinal problems, skin eruption, atrial fibrillation and asthenia, decreased peripheral blood stem cell yield during stem cell collection, venous thromboembolism, and secondary malignances. In this review we focused our attention on the cutaneous adverse reactions to lenalidomide.

Vitamin deficiency as risk factor for SARS-CoV-2 infection: correlation with susceptibility and prognosis.

OBJECTIVE: In 2019, an infection provoked by SARS-CoV-2 virus arose in Wuhan, China. Currently, there is still no definite and efficacious therapy for SARS-CoV-2 infection. Moreover, our understanding of the physiopathology of the infection, and risk elements for severity and mortality, is incomplete. PATIENTS AND METHODS: One largely neglected element that could affect prognosis of SARS-CoV-2 infection is the vitamin status of population. The purpose of this review is to evaluate whether a vitamin insufficiency could provoke an augmented risk of SARS-CoV-2 infection or the appearance of major complications. In particular, we evaluated the presence of studies related to the state and effects of vitamin D, C, B, and A in subjects with SARS-CoV-2 disease. RESULTS: Although, actually, the interest in a possible use for vitamin supplementation in SARS-CoV-2 patients is essentially based on indirect data, we tried to examine the evidence about a favorable effect of vitamin supplementation in the therapy of the infection and its complications. CONCLUSIONS: Supplements with vitamin A, B, C, D, and E could represent an inexpensive and sufficiently safe approach, and a useful therapeutic complement. However, solid clinical research data are expected to support such claim.

Antitumorigenic action of nelfinavir: Effects on multiple myeloma and hematologic malignancies (Review).

Protease inhibitors (PIs) inhibit HIV­1 and HIV­2 proteases, impeding virus replication and liberation of viral elements from infected cells. In human immunodeficiency virus (HIV) subjects receiving PI­based treatment, an impressive decrease in the amount of HIV­associated cancers, unconnected to viral burden or CD4 amount was observed. Research has reported that PIs have influence on cancer proliferation, spread, and survival as an effect on endoplasmic reticulum stress, proteasome, NF­κB and Akt signalling. Nelfinavir (NFV) is a nonpeptidic PI that functions by connecting to the catalytic site of the HIV protease, thus stopping the cleavage of viral polyprotein into complete, operative proteins that are fundamental for viral survival. NFV, currently not frequently employed for antiretroviral treatment, has demonstrated noteworthy off target effects in tumor patients with or without HIV disease. NFV appears to cause cell death in tumor cells by different mechanisms, which include necrosis, apoptosis and autophagy. In this review, data from preclinical research and clinical trials are reported and the mechanisms of action of NFV and their results in the treatment of hematologic malignancies, such as acute myeloid leukemia, chronic lymphoid leukemia, and diffuse large B cell lymphoma, and especially in patients with multiple myeloma are examined. In the future, experimental studies may help identify the role of NFV in cancer treatment and may promote the application of this drug into daily clinical practice.

[Our experience in inguinal hernia recurrences treatment]. / Il trattamento delle ernie inguinali recidive: nostra esperienza.

Reporting their personal experience, the authors focus on characteristics and causes of recurrence, either after traditional surgery or with tension-free technique. They describe difficulties and advantages in open interventions and laparoscopic ones. Facing a relapse it's convenient to assume an "eclectic" behaviour, thinking both of general and specific single patient anatomo-pathologic features.

Role of the microbiota in hematologic malignancies.

Human beings are inhabited by innumerable microorganisms that interrelate with the host in a reciprocal way, establishing a combined and efficient ecosystem - the microbiota - that can affect healthiness as well as disease. There is evidence that the conformation of the microbiota may influence, and is controlled by, the human immune system. Microbes existing in human tissues offer a multiplicity of advantages that participate in functional actions in the host through the adjustment of essential processes such as immunity, signal transduction, and metabolism. The imbalance of this microbial structure has been connected with the pathogenesis and progression of cancer. We reviewed the present knowledge of the diverse microbial ecosystems and we investigated their potential link to carcinogenesis, and the possibility of using advantageous microbes in controlling and preventing hematologic malignancies.

Bisphosphonate-associated osteonecrosis of the jaw in patients with multiple myeloma and breast cancer.

Osteonecrosis of the jaw is an unremitting adverse outcome associated with bisphosphonate therapy in patients with multiple myeloma or bone metastases from solid tumors. Twelve patients who presented with exposed bone associated with bisphosphonates were reviewed to determine the type, dosage and duration of their bisphosphonate therapy, presenting findings, comorbidities and the event that incited the bone exposure. The discontinuation of bisphosphonate therapy has not helped reverse the presence of osteonecrosis, and the surgical manipulation of the involved site appears to worsen the underlying bone pathology. Hyperbaric oxygen, which has proven efficacious in other forms of osteonecrosis by establishing an oxygen gradient, is of no definitive benefit to patients with bisphosphonate-induced exposed bone. Antibiotic therapy is useful in controlling pain and swelling but ineffective in preventing the progression of the exposed bone. To date, prevention is the only currently possible therapeutic approach to the management of this complication.

Amyloid myopathy presenting with rhabdomyolysis: evidence of complement activation.

At age of 57 years, a man experienced an episode of rhabdomyolysis. On that occasion muscle biopsy was not performed, however monoclonal gammopathy of undetermined significance (MGUS) was diagnosed. Further he developed a moderate proximal muscle weakness with CK level persistently elevated (1000-1200U/l). When he came to our observation, at age 67, a muscle biopsy revealed an amyloid myopathy and multiple myeloma was at the same time disclosed. Terminal complement complex C5b9 (membrane attack complex) deposits were found in the vessel walls and muscle fibers surface depicted by amyloid. Our case suggests to keep in mind the possibility that amyloid myopathy may begin as an isolate episode of rhabdomyolysis. The detection of complement complex C5b9 suggests that complement cascade is implicated in the muscular damage of amyloid myopathy.

Palliative antecolic isoperistaltic gastrojejunostomy: a randomized controlled trial comparing open and laparoscopic approaches.

Gastric outlet obstruction is a common, often preterminal, event for patients with inoperable neoplasms of the distal stomach, duodenum, and biliopancreatic area. It can be surgically managed by open or laparoscopic gastrojejunostomy. This study aimed to compare the results of open and laparoscopic palliative gastrojejunostomy for patients with gastric outlet obstruction resulting from inoperable neoplasms. A total of 24 patients were randomized prospectively to undergo laparoscopic (12 patients) or open (12 patients) palliative laterolateral antecolic isoperistaltic gastrojejunostomy. All the procedures were completed as planned. The mean duration of surgery was not significantly different between the two groups (p = 0.75). The mean intraoperative blood loss was significantly less after laparoscopic gastrojejunostomy (LGJ) (p = 0.0001). Time to oral solid food intake was longer after open gastrojejunostomy (OGJ) (p = 0.04). Two patients in the OGJ group experienced postoperative delayed gastric empting, whereas no patients in the LGJ group experienced such a complication (p = 0.04). The mean postoperative stay was shorter in the LGJ group, but the difference did not reach statistical significance (p = 0.65). No readmissions were registered after a minimum follow-up period of 2 months. The findings show that LGJ is a safe, feasible, and effective alternative to OGJ. However, because the current data involved only a small number of patients, large studies still are required for further evaluation of the this operation's effectiveness.

lncRNA profiling in early-stage chronic lymphocytic leukemia identifies transcriptional fingerprints with relevance in clinical outcome.

Long non-coding RNAs (lncRNAs) represent a novel class of functional RNA molecules with an important emerging role in cancer. To elucidate their potential pathogenetic role in chronic lymphocytic leukemia (CLL), a biologically and clinically heterogeneous neoplasia, we investigated lncRNAs expression in a prospective series of 217 early-stage Binet A CLL patients and 26 different subpopulations of normal B-cells, through a custom annotation pipeline of microarray data. Our study identified a 24-lncRNA-signature specifically deregulated in CLL compared with the normal B-cell counterpart. Importantly, this classifier was validated on an independent data set of CLL samples. Belonging to the lncRNA signature characterizing distinct molecular CLL subgroups, we identified lncRNAs recurrently associated with adverse prognostic markers, such as unmutated IGHV status, CD38 expression, 11q and 17p deletions, and NOTCH1 mutations. In addition, correlation analyses predicted a putative lncRNAs interplay with genes and miRNAs expression. Finally, we generated a 2-lncRNA independent risk model, based on lnc-IRF2-3 and lnc-KIAA1755-4 expression, able to distinguish three different prognostic groups in our series of early-stage patients. Overall, our study provides an important resource for future studies on the functions of lncRNAs in CLL, and contributes to the discovery of novel molecular markers with clinical relevance associated with the disease.

A phase 2 study of three low-dose intensity subcutaneous bortezomib regimens in elderly frail patients with untreated multiple myeloma.

This phase 2 trial evaluated three low-dose intensity subcutaneous bortezomib-based treatments in patients ⩾75 years with newly diagnosed multiple myeloma (MM). Patients received subcutaneous bortezomib plus oral prednisone (VP, N=51) or VP plus cyclophosphamide (VCP, N=51) or VP plus melphalan (VMP, N=50), followed by bortezomib maintenance, and half of the patients were frail. Response rate was 64% with VP, 67% with VCP and 86% with VMP, and very good partial response rate or better was 26%, 28.5% and 49%, respectively. Median progression-free survival was 14.0, 15.2 and 17.1 months, and 2-year OS was 60%, 70% and 76% in VP, VCP, VMP, respectively. At least one drug-related grade ⩾3 non-hematologic adverse event (AE) occurred in 22% of VP, 37% of VCP and 33% of VMP patients; the discontinuation rate for AEs was 12%, 14% and 20%, and the 6-month rate of toxicity-related deaths was 4%, 4% and 8%, respectively. The most common grade ⩾3 AEs included infections (8-20%), and constitutional (10-14%) and cardiovascular events (4-12%); peripheral neuropathy was limited (4-6%). Bortezomib maintenance was effective and feasible. VP, VCP and VMP regimens demonstrated no substantial difference. Yet, toxicity was higher with VMP, suggesting that a two-drug combination followed by maintenance should be preferred in frail patients.

High rate of recurrent venous thromboembolism in patients with myeloproliferative neoplasms and effect of prophylaxis with vitamin K antagonists.

The optimal duration of treatment with vitamin K antagonists (VKA) after venous thromboembolism (VTE) in patients with Philadelphia-negative myeloproliferative neoplasms (MPNs) is uncertain. To tackle this issue, we retrospectively studied 206 patients with MPN-related VTE (deep venous thrombosis of the legs and/or pulmonary embolism). After this index event, we recorded over 695 pt-years 45 recurrences, venous in 36 cases, with an incidence rate (IR) of 6.5 per 100 pt-years (95% confidence interval (CI): 4.9-8.6). One hundred fifty-five patients received VKA; the IR of recurrent thrombosis per 100 pt-years was 4.7 (95% CI: 2.8-7.3) on VKA and 8.9 (95% CI: 5.7-13.2) off VKA (P=0.03). In patients receiving VKA, the IR of recurrent thrombosis per 100 pt-years was 5.3 (95% CI: 3.2-8.4) among 108 patients on long-term VKA and 12.8 (95% CI: 7.3-20.7) after discontinuation among the 47 who ceased treatment (P=0.008), with a doubled risk of recurrence after stopping VKA (hazard ratio: 2.21, 95% CI: 1.19-5.30). The IR of major bleeding per 100 pt-years was 2.4 (95%: CI: 1.1-4.5) on VKA and 0.7 (95% CI: 0.08-2.5) off VKA (P=0.08). In conclusion, in MPN patients with VTE recurrent thrombosis is significantly reduced by VKA and caution should be adopted in discontinuation; however, the incidence of recurrence on treatment remains high, calling for clinical trials aimed to improve prophylaxis in this setting.

Splanchnic vein thrombosis in myeloproliferative neoplasms: risk factors for recurrences in a cohort of 181 patients.

We retrospectively studied 181 patients with polycythaemia vera (n=67), essential thrombocythaemia (n=67) or primary myelofibrosis (n=47), who presented a first episode of splanchnic vein thrombosis (SVT). Budd-Chiari syndrome (BCS) and portal vein thrombosis were diagnosed in 31 (17.1%) and 109 (60.3%) patients, respectively; isolated thrombosis of the mesenteric or splenic veins was detected in 18 and 23 cases, respectively. After this index event, the patients were followed for 735 patient years (pt-years) and experienced 31 recurrences corresponding to an incidence rate of 4.2 per 100 pt-years. Factors associated with a significantly higher risk of recurrence were BCS (hazard ratio (HR): 3.03), history of previous thrombosis (HR: 3.62), splenomegaly (HR: 2.66) and leukocytosis (HR: 2.8). Vitamin K-antagonists (VKA) were prescribed in 85% of patients and the recurrence rate was 3.9 per 100 pt-years, whereas in the small fraction (15%) not receiving VKA more recurrences (7.2 per 100 pt-years) were reported. Intracranial and extracranial major bleeding was recorded mainly in patients on VKA and the corresponding rate was 2.0 per 100 pt-years. In conclusion, despite anticoagulation treatment, the recurrence rate after SVT in myeloproliferative neoplasms is high and suggests the exploration of new avenues of secondary prophylaxis with new antithrombotic drugs and JAK-2 inhibitors.

Lymphoproliferative disease and cancer among patients with common variable immunodeficiency.

Innate immune deficiencies are a heterogeneous group of genetically inherited diseases affecting the innate and adaptive immune systems that confer susceptibility to infection, autoimmunity, and cancer. This review discusses the latest insights into the links between common variable immunodeficiency (CVI) and malignancies. Although Ig therapy greatly reduces the number of infections and enhances survival, it does not appear to address the development of cancer, especially lymphoma. The reasons for the increased susceptibility to lymphoid malignancies are unclear. These include genetics, immune dysregulation, radiosensitivity and chronic infections such as Helicobacter pylori, EBV, human herpes virus type 8 and cytomegalovirus. Further studies will allow us to better stratify the risk for cancer in these patients, and teach us to better prevent these complications and to better treat them.

Vaccination strategies in lymphoproliferative disorders: Failures and successes.

Anti-tumor vaccines in lymphoproliferative disorders hold out the prospect of effective tumor therapies with minimal side effects. The addition of immunotherapy to old and new chemotherapy regimens has improved both response rates and disease-free survival, leading in many cases to an extended overall survival. Ideally, an antigen that is used for vaccination would be specifically expressed in the tumor; it must have an important, causal part in the multifactorial process that leads to cancer, and it must be expressed stably even after it is attacked by the immune system. Immunotherapies, which aim to activate the immune system to kill cancer cells, include strategies to increase the frequency or potency of antitumor T cells, to overcome suppressive factors in the tumor microenvironment, and to reduce T-cell suppression systemically. In this review, we focus on the results of clinical trials of vaccination in lymphoma, and discuss potential strategies to enhance the efficacy of immunotherapy in the future.

Intracellular and serum levels of aldolase activity in B chronic lymphocytic leukemia.

Intracellular and serum activities of aldolase (ALS) were biochemically determined in lymphocyte subpopulations from normal subjects and patients with B-chronic lymphocytic leukemia (B-CLL). Aldolase activity was significantly lower in T cells of CLL than in normal T cells (2.9 +/- 1.5 vs. 4.7 +/- 2.1 Sigma Units (SU)/6 x 10(6) cells, p < 0.05). The aldolase activity also was significantly (p < 0.001) lower (3.1 +/- 1.9 SU/6 x 10(6) cells) in CLL B lymphocytes than in normal B lymphocytes (18.1 +/- 6.5 SU/6 x 10(6) cells). Moreover, the serum levels of ALS in all patients with B-CLL were higher than that in normal subjects (8.1 +/- 5.8 vs. 2.2 +/- 0.8 SU/ml, p < 0.02). Our findings demonstrate that T lymphocytes from patients with B-CLL display enzyme activity different from that of normal T cells. This may reflect the abnormal maturity of the residual T cell population in B-CLL.

Isodicentric Philadelphia chromosome in accelerated phase of chronic myeloid leukemia.

We describe a case of chronic myeloid leukemia (CML) associated with the finding of an isodicentric Philadelphia chromosome [idic(Ph)] during the accelerated phase of the disease. Chromosome study was carried out on bone marrow aspirate cells, obtained and cultured 5 months after the clinical diagnosis. The presence of an isodicentric Philadelphia chromosome was found in 90% of the analyzed metaphases; among the remaining observed metaphases, 6% showed two idic(Ph) chromosomes, 2% a t(9;22), and 2% a normal karyotype. The patient died 7 months after the clinical diagnosis, and 2 months after our chromosome study. The observation of idic(Ph) during CML has seldom been reported and the few cases studied have been inconsistently correlated with the course of the disease. In the present case, the finding of an idic(Ph) and the short patient survival from the time of clinical diagnosis may suggest the observed chromosome aberration as a factor associated with a poor prognosis.

Translocation (5;10)(q13;q26) in acute monoblastic leukemia.

We report a case of acute monoblastic leukemia [French-American-British (FAB) M5a] observed in a 38-year-old man and associated at diagnosis with a t(5;10)(q13;q26) found in cells from a bone marrow culture. The patient survived only 2 months after diagnosis. t(5;10) as a solitary chromosome abnormality has not been previously reported in M5a, and, in the case that we describe, it appears to be correlated with a poor prognosis.

Leukocyte integrin very late antigen-4/vascular cell adhesion molecule-1 adhesion pathway in splanchnic artery occlusion shock.

We investigated the role played by the very late antigen-4 (VLA-4)/ vascular cell adhesion molecule-1 (VCAM-1) interaction in the pathogenesis of splanchnic artery occlusion shock. Splanchnic artery occlusion shock was induced in anaesthetized rats by clamping splanchnic arteries for 45 min. Sham operated animals were used as controls. Survival time, serum tumour necrosis factor (TNF-alpha), monocyte and lymphocyte cell count and the responsiveness to acetylcholine of aortic rings were studied. Furthermore we investigated the VCAM-1 expression on vessel endothelium and the percentage of VLA-4 positive leukocytes. Splanchnic artery occlusion shocked rats had a decreased survival time (76 +/- 10 min, while sham shocked rats survived more than 4 h), increased serum levels of TNF-alpha (328 +/- 11 U/ml), a decreased number of both monocytes and lymphocytes and reduced responsiveness to acetylcholine (10 nM-10 microM) of aortic rings. In addition we found an increased expression of endothelial VCAM-1 on aortic rings and a reduced percentage of VLA-4 positive lymphocytes and monocytes. Passive immunization with specific antibodies raised against either VCAM-1 or VLA-4 (2 mg/kg, i.v., 3 h before splanchnic artery occlusion shock) increased survival, improved monocyte and lymphocyte count and restored the responsiveness of aortic rings to acetylcholine (P < 0.01). Finally, inhibition of TNF-alpha biosynthesis reversed the increased endothelial expression of VCAM-1 and the reduced percentage of integrin VLA-4 positive leukocytes. Our findings suggest that (i) VLA-4/VCAM-1 interaction has a role in the pathogenesis of circulatory shock; (ii) this interaction might be a target for new therapeutic approaches to the therapy of low-flow states.