Daratumumab plus bortezomib or daratumumab plus lenalidomide as salvage therapy for patients with myeloma: initial follow-up of an Italian multicentre retrospective clinical experience by 'Rete Ematologica Pugliese'.

We report herein a multicentre retrospective analysis of 192 consecutive patients with symptomatic refractory/relapsed multiple myeloma (RRMM) treated with daratumumab in combination with bortezomib or lenalidomide as salvage therapy at 9 haematological centres in Puglia. Choice of both regimens was based on previous treatment and/or physicians' preference. Considering the under-representation of older patients (very old patient ≥ 80 years) in clinical trials and the prognostic and predictive importance and value of frailty status, here, we further characterised the patient cohort by age. The overall response rate (ORR) was generally lower than what was previously reported in the CASTOR (ORR 72.6% vs 85%) and POLLUX (ORR 86.5% vs 93%) trials. The lower ORR in our analysis compared to the CASTOR and POLLUX trials could be related to a less selected population. Similarly, amongst very old patients, the ORR was encouraging: ORR to treatment with DVd (daratumumab + bortezomib + dexamethasone) was 66.7%, and ORR to treatment with DRd (daratumumab + lenalidomide + dexamethasone) was 92.3%. Median TTP (time to progression) was 10.8 months (1-year TTP: 44.7%; 2-year TTP: 25.3%) in the DVd group; median TTP was not reached in the DRd group (1-year TTP: 82.7%; 2-year TTP: 71.4%). Median OS (overall survival) was not reached either in the DRd group (1-year OS: 85.9%; 2-year OS: 73.7%) or the DVd group (1-year OS: 70.2%; 2-year OS: 58.9%).

Fungal infections of the central nervous system and paranasal sinuses in onco-haematologic patients. Epidemiological study reporting the diagnostic-therapeutic approach and outcome in 89 cases.

Invasive fungal infections (IFI) of the Central Nervous System (IFI-CNS) and Paranasal Sinuses (IFI-PS) are rare, life-threatening infections in haematologic patients, and their management remains a challenge despite the availability of new diagnostic techniques and novel antifungal agents. In addition, analyses of large cohorts of patients focusing on these rare IFI are still lacking. Between January 2010 and December 2016, 89 consecutive cases of Proven (53) or Probable (36) IFI-CNS (71/89) and IFI-PS (18/89) were collected in 34 haematological centres. The median age was 40 years (range 5-79); acute leukaemia was the most common underlying disease (69%) and 29% of cases received a previous allogeneic stem cell transplant. Aspergillus spp. were the most common pathogens (69%), followed by mucormycetes (22%), Cryptococcus spp. (4%) and Fusarium spp. (2%). The lung was the primary focus of fungal infection (48% of cases). The nervous system biopsy was performed in 10% of IFI-CNS, and a sinus biopsy was performed in 56% of IFI-PS (P = 0.03). The Galactomannan test on cerebrospinal fluid has been performed in 42% of IFI-CNS (30/71), and it was positive in 67%. Eighty-four pts received a first-line antifungal therapy with Amphotericine B in 58% of cases, Voriconazole in 31% and both in 11%. Moreover, 58% of patients received 2 or more lines of therapy and 38% were treated with a combination of 2 or more antifungal drugs. The median duration of antifungal therapy was 60 days (range 5-835). A surgical intervention was performed in 26% of cases but only 10% of IFI-CNS underwent neurosurgical intervention. The overall response rate to antifungal therapy (complete or partial response) was 57%, and 1-year overall survival was 32% without significant differences between IFI-CNS and IFI-PS. The overall mortality was 69% but the IFI attributable mortality was 33%. Mortality of IFI-CNS/PS remains high but, compared to previous historical data, it seems to be reduced probably due to the availability of newer antifungal drugs. The results arising from this large contemporary cohort of cases may allow a more effective diagnostic and therapeutic management of these very rare IFI complications in haematologic patients.

Multicentre surveillance study on feasibility, safety and efficacy of antifungal combination therapy for proven or probable invasive fungal diseases in haematological patients: the SEIFEM real-life combo study.

UNLABELLED: This multicentre observational study evaluated the feasibility, efficacy and toxicity of antifungal combination therapy (combo) as treatment of proven or probable invasive fungal diseases (IFDs) in patients with haematological malignancies. Between January 2005 and January 2010, 84 cases of IFDs (39 proven and 45 probable) treated with combo were collected in 20 Hematological Italian Centres, in patients who underwent chemotherapy or allogeneic haematopoietic stem cell transplantation for haematological diseases. Median age of patients was 34 years (range 1-73) and 37% had less than 18 years. Acute leukaemia was the most common underlying haematological disease (68/84; 81%). The phase of treatment was as follows: first induction in 21/84 (25%), consolidation phase in 18/84 (21%) and reinduction/salvage in 45/84 (54%). The main site of infection was lung with or without other sites. The principal fungal pathogens were as follows: Aspergillus sp. 68 cases (81%), Candida sp. six cases (8%), Zygomycetes four cases (5%) and Fusarium sp. four cases (5%). The most used combo was caspofungin+voriconazole 35/84 (42%), caspofungin + liposomal amphotericin B (L-AmB) 20/84 (24%) and L-AmB+voriconazole 15/84 (18%). The median duration of combo was 19 days (range 3-180). The overall response rate (ORR) was 73% (61/84 responders) without significant differences between the combo regimens. The most important factor that significantly influenced the response was granulocyte (PMN) recovery (P 0.009). Only one patient discontinued therapy (voriconazole-related neurotoxicity) and 22% experienced mild and reversible adverse events (hypokalaemia, ALT/AST increase and creatinine increase). The IFDs-attributable mortality was 17%. This study indicates that combo was both well tolerated and effective in haematological patients. The most used combo regimens were caspofungin + voriconazole (ORR 80%) and caspofungin + L-AmB (ORR 70%). The ORR was 73% and the mortality IFD related was 17%. PMN recovery during combo predicts a favourable outcome. CLINICAL TRIALS REGISTRATION: NCT00906633.

Surface recrystallization of polyethylene extended-chain crystals.

Rough fracture surfaces of extended-chain polyethylene crystals become unstable at temperatures below the bulk melting point. There is no way for the extended chains, which are up to 20,000 methylene units long, to change position without collapse. As a result, the rough surfaces smooth out on heating by covering themselves with oriented folded-chain lamellae.

Fungal infections in recipients of hematopoietic stem cell transplants: results of the SEIFEM B-2004 study--Sorveglianza Epidemiologica Infezioni Fungine Nelle Emopatie Maligne.

BACKGROUND: The purpose of our study was to evaluate the incidence and outcome of invasive fungal infection (IFI) among patients who underwent autologous or allogeneic hematopoietic stem cell transplantation (HSCT) at 11 Italian transplantation centers. METHODS: This cohort-retrospective study, conducted during 1999-2003, involved HSCT patients admitted to 11 tertiary care centers or university hospitals in Italy, who developed IFIs (proven or probable). RESULTS: Among 3228 patients who underwent HSCT (1249 allogeneic HSCT recipients and 1979 autologous HSCT recipients), IFI occurred in 121 patients (overall incidence, 3.7%). Ninety-one episodes (2.8% of all patients) were due to molds, and 30 (0.9%) were due to yeasts. Ninety-eight episodes (7.8%) occurred among the 1249 allogeneic HSCT recipients, and 23 (1.2%) occurred among the 1979 autologous HSCT recipients. The most frequent etiological agents were Aspergillus species (86 episodes) and Candida species (30 episodes). The overall mortality rate was 5.7% among allogeneic HSCT recipients and 0.4% among autologous HSCT recipients, whereas the attributable mortality rate registered in our population was 65.3% (72.4% for allogeneic HSCT recipients and 34.7% for autologous HSCT recipients). Etiology influenced the patients' outcomes: the attributable mortality rate for aspergillosis was 72.1% (77.2% and 14.3% for allogeneic and autologous HSCT recipients, respectively), and the rate for Candida IFI was 50% (57.1% and 43.8% for allogeneic and autologous HSCT recipients, respectively). CONCLUSIONS: IFI represents a common complication for allogeneic HSCT recipients. Aspergillus species is the most frequently detected agent in these patients, and aspergillosis is characterized by a high mortality rate. Conversely, autologous HSCT recipients rarely develop aspergillosis, and the attributable mortality rate is markedly lower. Candidemia was observed less often than aspergillosis among both allogeneic and autologous HSCT recipients; furthermore, there was no difference in either the incidence of or the attributable mortality rate for candidemia among recipients of the 2 transplant types.

Beneficial Effects of Applying Low-Level Laser Therapy to Surgical Wounds After Bariatric Surgery.

BACKGROUND: Bariatric surgery is a successful method for weight loss in cases of morbid obesity; however, as an invasive procedure, surgical complications may occur. Low-level laser therapy (LLLT) has been increasingly used due to its effectiveness in controlling the inflammatory response, accelerating tissue repair, and reducing pain. The objective of this study was to investigate photobiomodulation effects after bariatric surgery and determine the laser actions during the inflammatory process, wound healing (clinical observation), and analgesia. METHODS: This study was a randomized, placebo-controlled, clinical trial in which 85 patients underwent Roux en-Y gastric bypass (RYGB) by conventional techniques (i.e., open surgery). Patients were divided into two groups and were irradiated with LLLT at 10 different points through the surgical scar in three sessions of applications: the laser group (laser-on) consisted of 43 patients who received the CW diode laser (MMOptics), while the placebo group (laser-off) consisted of 42 patients who were treated by the same protocol but with a disabled laser. Temperature was measured by a digital thermometer in both groups, and pain was evaluated using the visual analogue scale for pain. Biochemical analysis and digital images were used to document and evaluate the inflammatory response as well as tissue repair process at the surgical wound site. RESULTS: Patients in the laser group demonstrated diminished wound temperature as erythrocyte sedimentation rate (ESR) compared with the placebo group, indicating better inflammatory process control as well as improved wound healing and reduced pain. CONCLUSIONS: LLLT applied with the described protocol led to a decrease by biochemical markers and wound temperature compared with the placebo, which indicated that LLLT was able to control the inflammatory process; in addition, seroma and pain were reduced and cicatrization was improved by this preventive procedure.

Prognostic relevance of serum beta 2-microglobulin in acute myeloid leukemia.

Serum levels of beta 2-microglobulin (S-B2m) were analysed at diagnosis in 69 cases of acute myeloid leukemias (AML) as a possible prognostic indicator. S-B2m was correlated to various clinical and laboratory features and with respect to response to chemotherapy and following clinical outcome. S-B2m was found to be increased (greater than 3 mg/l) in 40.6% of tested patients and, in particular, in the monocytic variants (M4, M5) of AML (4.2 versus 2.3 mg/l, p less than 0.01). S-B-B2m values paralleled white blood cell count, serum lysozyme levels and expression of monocytic membrane markers at presentation, but no correlation was found with age, renal function or immunological myeloid antigens. Increased levels of S-B2m were associated with a lower likelihood of obtaining a complete remission (25 versus 58.5%, p less than 0.01), while in the multivariate analysis S-B2m greater than 3 mg/l and white blood cell count greater than 20 x 10(9)/l were independent variables significantly influencing disease-free survival in responsive patients (five years DFS for S-B2m greater than or less than 3 mg/l: 28 versus 62%, p less than 0.05). In conclusion, the measurement of S-B2m at diagnosis may have prognostic relevance in AML.

Effective autologous peripheral blood stem cell transplantation in plasma cell leukemia followed by T-large granular lymphocyte expansion: a case report.

We report a case of de novo plasma cell leukemia, resistant to standard VMD (vincristine, mitoxantrone, dexamethasone) and CVP (cyclophosphamide, vincristine and prednisone) protocols, treated with a chemotherapy intensification regimen (high-dose cyclophosphamide, modified EDAP, Dexa-BEAM) and peripheral blood stem cell transplantation, performed using fractionated total body irradiation and high dose melphalan. The patient is currently alive and well, in very good partial remission 12 months after transplant and 22 months after diagnosis, disclosing a significant proportion of bone marrow and peripheral blood CD3+, CD8+, CD57+, HLA-Dr+ large granular lymphocytes with cytotoxic activity against neoplastic plasma cells.

Minimally differentiated acute myeloid leukemia (AML M0): clinico-biological findings of 29 cases.

Twenty-nine cases of minimally differentiated acute myeloid leukemia or AML M0 identified among 441 AML diagnosed in the last 12 years are reported. In all cases, flow cytometric analysis using a large panel of monoclonal antibodies and cytogenetic and molecular studies (IgH, TcRbeta, BCR/ABL, AML1/ETO and CBFB-MYH11 rearrangements) were performed. Of the 29 patients, 27 were treated with intensive chemotherapy based on GIMEMA protocols. We noted a greater incidence of older (over 60 years) and male patients (52% and 65%, respectively). CD33, CD13, CD7 and TdT were expressed in 79.3%, 82.7%, 58.6% and 42.8% of cases, respectively. Antigenic MPO was present in 17 of 22 cases (77.3%). Most cases expressed CD34 (93.1%), HLA-DR (93.1%), CD117 (80%) and CD45RA (87%). CD45RO and CD90 were consistently negative. In all cases, we observed an up-expression of bcl-2 and a down-expression of CD95 with an inverse trend between the two markers (r -5253; p 0.03). Karyotypic abnormalities were demonstrated in 53.6% of cases. Of these, 6 involved chromosomes 5, 7 and 8, t(9;22), confirmed by the BCR/ABL transcript, was detected in one case. Rearrangements of the TcRbeta and IgH chains were observed in 3 and 2 cases, respectively. No AML1/ETO and CBFB-MYH11 transcripts were found. Twelve out of 27 patients (44%) achieved a complete remission (CR) (in 2 cases after rescue therapy). Seven early (range 1-9 months) and one late (32 months) relapses were observed. Five patients are alive, but only the 4 who underwent bone marrow transplantation are in persistent first CR. In conclusion, AML M0 is a subtype of AML antigenically well detectable, endowed with many adverse parameters (older age, TdT and CD34 expression, resistance to apoptosis, unfavorable cytogenetic abnormalities) and poor prognosis. A very aggressive consolidation treatment can be useful to improve the outcome.

Are "early" and "late" T-acute lymphoblastic leukemias different diseases? A single center study of 34 patients.

Clinical and biological parameters were retrospectively reviewed in 34 cases of T-lineage acute lymphoblastic leukemia (T-ALL), classified as "early" (20 cases) or "late" (14 cases) subgroups, according to the degree of blast cell differentiation, assessed by immunophenotyping. In "early" T-ALL, age, co-expression of "immature" (CD34 and HLA-Dr) or myeloid (My+) antigens, proliferative activity (as evaluated by Ki67 monoclonal antibody), and expression of the "multidrug-resistance" (MDR) phenotype (as determined by C-219 monoclonal antibody) were significantly higher, while WBC count and expression of CDl0 were significantly lower, than in "late" T-ALL. Furthermore, although no statistically significant difference was found between the two groups, "late" T-ALL more frequently displayed a greater extramedullary tumor mass ("lymphoma-like" syndrome), LI FAB morphology and a normal karyotype. A single patient, with "late" T-ALL, also showed positivity for TCR gamma/delta chains, specific monoclonal antibodies. On the whole, 30 patients (88.2%) achieved complete remission: 16(80%) were "early" and 14(100%) "late" T-ALL. No statistical difference was found between the two groups with respect to disease free survival (42% vs 54% at six years), whereas median overall survival was significantly shorter in "early" T-ALL (23 months vs median not yet reached at six years for "late" T-ALL, p < 0.05). We conclude that "early" and "late" T-ALL show clinical and biological differences, that could perhaps justify differential therapeutic approaches.

Treatment of "poor risk" acute myeloid leukemia with fludarabine, cytarabine and G-CSF (flag regimen): a single center study.

We describe a single center experience of 41 consecutive patients with poor prognosis acute myeloid leukemia (AML) who received a single course of FLAG regimen consisting of Fludarabine 30 mg/m2/day plus Cytarabine 2 gr/m2/day (days 1-5) and G-CSF 5 mg/Kg/day (from day 0 to polymorphonuclear recovery) as salvage therapy. Eleven patients were primarily refractory to previous chemotherapy, 10 patients were in first relapse, 2 patients in second relapse and 7 patients in relapse after transplants. Eleven cases were defined as secondary AML (diagnosis of AML made after a preexisting diagnosis of myelodysplastic syndrome). The median age was 52.6 years (range 16-72); 29 patients were males and 12 females. Overall, 23 (56%) patients reached complete remission (CR), 3 patients died of infection (2) or hemorrhage (1) during induction, and 15 (36%) patients had resistant disease. The highest CR rates (80%) were obtained in relapsed cases; de novo and secondary AML registered 60% and 45% of CR rates, respectively. Patients achieving CR received a second FLAG course as consolidation and were submitted to an individualized program post-remission therapy, depending on the age and performance status. Hematological and non hematological toxicities were acceptable. In conclusion, our data confirm that FLAG is a an high effective treatment for poor prognosis AML and in young patients allows intensive post remissional therapy including allogeneic BMT.

Serum beta 2-microglobulin in malignant lymphoproliferative disorders.

Beta 2-microglobulin (B2m) was measured on serum samples in 274 patients with acute and chronic lymphoproliferative disorders (85 non-Hodgkin lymphomas-NHL, 30 Hodgkin lymphomas-HL, 34 B-cell chronic lymphocytic leukemias-B-CLL, 8 Waldenström macroglobulinemias-WM, 76 multiple myelomas-MM, 31 acute lymphoblastic leukemias-ALL, 10 hairy cell leukemias-HCL). Two hundred and four patients were studied at the time of diagnosis, and results were correlated to clinical stage, and histologic subtype in NHL, immunoglobulin type in MM, and immunologic phenotype in ALL. Moreover, B2m was tested during and after chemo- and/or radiotherapy, and results were correlated to response, progression or relapse. Elevated pretreatment B2m values were found in widespread forms of NHL and HL, in patients with B symptoms and in the unfavorable histologic subgroups of NHL. Rapid falls in levels followed therapy institution. In B-CLL and in MM a close relationship between B2m and cell mass was found. A significant B2m level reduction followed treatment, whereas its increase could detect a relapse. In ALL, serum B2m was only slightly above the normal range. B2m seems to reflect the total burden of malignant cells mainly in MM and B-CLL; in other lymphoproliferative disorders it provides less prognostic information.

Cutaneous presentation of acute myeloid leukemia in a "classical" Kaposi's sarcoma patient.

A case of early cutaneous involvement by an acute myeloid leukemia in a Caucasian man, previously affected by a "classical" Kaposi's sarcoma is reported. The diagnoses were based upon histologic examinations and appropriate hematologic investigations. After reviewing extensively the literature about the association of lymphoreticular system malignancies and Kaposi's sarcoma, possible implications and hypothetical etiopathogenetic mechanisms are discussed.

Clinical relevance of immunocytochemical detection of multidrug-resistance-associated P-glycoprotein in hematologic malignancies.

P-glycoprotein (P-170) is the phenotypic marker of tumoral cells that show the phenomenon of multidrug resistance (MDR). Using an immunocytochemical approach, we employed the monoclonal antibody C219 (which recognizes an epitope of such a glycoprotein) to evaluate in cytologic samples the expression of P-170 on neoplastic cells from 52 patients affected by different hematologic malignancies and its eventual correlation to clinical outcome. Longitudinal studies were also performed in 14 patients. Results obtained demonstrated that a) the so-called "MDR phenotype" may be heterogeneously represented (from less than 1 to 100% of positive cells) in hemopoietic tumors at diagnosis (without exposure to pharmacologic agents), as well as during the course of the disease, although a more substantial presence of P-170 occurred in treated patients. There was no correlation between neoplastic kinetic activity (such as expression of Ki 67 recognized nuclear proliferation-associated antigen) and P-170-positive cells. b) Percentage of positive cells as well as intensity of staining seemed to be important in determining MDR; in general, there was a strong correlation between expression of P-170 in more than 20% of neoplastic cells and a lack of response to chemotherapy. However, some false-positive and false-negative cases were observed. c) The detection of scattered P-170-positive cells may predict a pharmacologic selection of intrinsic or mutant-resistant clones.

Comparative molecular analysis of therapy-related and de novo acute promyelocytic leukemia.

Therapy-related acute promyelocytic leukemia (t-APL) has been reported as a late complication of exposure to radiotherapy and/or chemotherapeutic agents targeting DNA topoisomerase II. We have analyzed in t-APL novel gene mutations recently associated with myeloid disorders. Unlike previous reports in acute myeloid leukemia (AML), our results showed neither IDHs nor TET2 mutations in t-APL. However we found an R882H mutation in the DNMT3A gene in a patient with t-APL suggesting a possible role of this alteration in the pathogenesis of t-APL.

Diuretic plants in the paintings of Pompeii.

The plants that appear in the paintings and mosaics of Pompeii are chiefly edible and medicinal, though flowers with purely esthetic appeal are also shown. An important example is one of the floor mosaics from the House of the Faun, in which it is possible to identify lemon, cherry, strawberry, pomegranate, grape and olive, leaves of grape, fig, apple and olive, and flowers of corn cockle. The diuretic properties of some of these plants are mentioned in the Naturalis Historia of Pliny the Elder. A silver cup from the House of Menandro, one of the most refined examples of plant decoration in antiquity, shows olive branches and fruits. The presence of plants in such artefacts confirms that people of classical times were conscious that plants were important producers of food, oils, fibers, woods and medicines.

[Thermalism in ancient world]. / Il termalismo nel mondo antico.

The importance of water was well known in Prehistory and in ancient World. There are, in Homeric poems, several descriptions of cold and warm baths, a witness of their utilization in ancient Greek civilization. But the sources of water were always linked with the divinities of the Earth, and the temples dedicated to Asklepios had also thermal baths. The Romans, heirs of Etruscan culture, made the baths a social and public matter, and in Rome the Thermate reached a high degree of perfection.