Impact of CR before and after allogeneic and autologous transplantation in multiple myeloma: results from the EBMT NMAM2000 prospective trial.

Previous studies have shown that obtaining complete hematologic remission (CR) in multiple myeloma is an important predictor of PFS and OS. This applies both to autologous and allogeneic transplantation. However, the importance of CR obtained before vs after second transplant or following allogeneic vs autologous transplantation is not clear. We investigated the role of CR analyzing data from the EBMT-NMAM2000 interventional prospective study comparing tandem autologous/reduced intensity conditioning allogeneic transplantation (auto/RICallo) to autologous transplantation-single or double (auto/auto). Allocation to treatment was performed according to availability of a matched sibling donor. Cox regression and multi-state models were applied. The long-term probability of survival in CR was superior in auto/RICallo, both comparing groups according to treatment allocated at start (28.8 vs 11.4% at 60 months, P=0.0004) and according to actual administration of second transplant (25.6 vs 9.6% at 60 months, P=0.008). CR achieved before the second transplant was predictive for PFS (hazard ratio (HR)=0.44, P= 0.003) and OS (HR 0.51, P=0.047) irrespective of the type of second transplant. CR achieved after auto/RICallo was more beneficial for PFS (HR=0.53, P=0.027) than CR after auto/auto (HR=0.81, P=0.390), indicating a better durability of CR obtained after an allotransplant procedure.

Allogeneic transplantation following a reduced-intensity conditioning regimen in relapsed/refractory peripheral T-cell lymphomas: long-term remissions and response to donor lymphocyte infusions support the role of a graft-versus-lymphoma effect.

Rescue chemotherapy or autologous stem cell transplantation (autoSCT) gives disappointing results in relapsed peripheral T-cell lymphomas (PTCLs). We have retrospectively evaluated the long-term outcome of 52 patients receiving allogeneic SCT for relapsed disease. Histologies were PTCL-not-otherwise specified (n=23), anaplastic large-cell lymphoma (n=11), angioimmunoblastic T-cell lymphomas (n=9) and rare subtypes (n=9). Patients were allografted from related siblings (n=33, 64%) or alternative donors (n=13 (25%) from unrelated and 6 (11%) from haploidentical family donors), following reduced-intensity conditioning (RIC) regimens including thiotepa, fludarabine and cyclophosphamide. Most of the patients had chemosensitive disease (n=39, 75%) and 27 (52%) failed a previous autoSCT. At a median follow-up of 67 months, 27 of 52 patients were found to be alive (52%) and 25 (48%) were dead (n=19 disease progression, n=6 non-relapse mortality (NRM)). The cumulative incidence (CI) of NRM was 12% at 5 years. Extensive chronic graft-versus-host disease increased the risk of NRM (33% versus 8%, P=0.04). The CI of relapse was 49% at 5 years, influenced by disease status at the time of allografting (P=0.0009) and treatment lines (P=0.007). Five-year overall survival and progression-free survival (PFS) were 50% (95% CI, 36 - 63%) and 40% (95% CI, 27 - 53%), respectively. The current PFS was 44% (95% CI, 30-57%). In all, 8 out of 12 patients (66%) who received donor-lymphocytes infusions for disease progression had a response. At multivariable analysis, refractory disease and age over 45 years were independent adverse prognostic factors. RIC allogeneic SCT is an effective salvage treatment with a better outcome for younger patients with chemosensitive disease.

Prevalence of human herpesvirus-6 chromosomal integration (CIHHV-6) in Italian solid organ and allogeneic stem cell transplant patients.

The unique phenomenon of human herpesvirus-6 (HHV-6) chromosomal integration (CIHHV-6) may account for clinical drawbacks in transplant setting, being misinterpreted as active infection and leading to unnecessary and potentially harmful treatments. We have investigated the prevalence of CIHHV-6 in 205 consecutive solid organ (SO) and allogeneic stem cell transplant (alloSCT) Italian patients. Fifty-two (38.5%) of 135 solid organ transplant (SOT) and 16 (22.8%) of 70 alloSCT patients resulted positive for plasma HHV-6 DNA by real-time polymerase chain reaction. Seven SOT and three alloSCT patients presented HHV-6-related diseases, requiring antivirals. Two further patients (0.9%) were identified, presenting high HHV-6 loads. The quantification of HHV-6 on hair follicles disclosed the integrated state, allowing the discontinuation of antivirals. Before starting specific treatments, CIHHV-6 should be excluded in transplant patients with HHV-6 viremia by the comparison of HHV-6 loads on different fluids and tissues. Pretransplantation screening of donors and recipients may further prevent the misdiagnosis of CIHHV-6.

Allogeneic stem cell transplantation following reduced-intensity conditioning can induce durable clinical and molecular remissions in relapsed lymphomas: pre-transplant disease status and histotype heavily influence outcome.

The safety and efficacy of reduced-intensity conditioning (RIC) followed by allogeneic stem cell transplantation (SCT) for relapsed lymphomas remains unresolved. We conducted a prospective, multicentered, phase II trial. A total of 170 relapsed/refractory lymphomas received a RIC regimen followed by SCT from sibling donors. The primary study end point was non-relapse mortality (NRM). Histologies were non-Hodgkin's lymphomas (NHL) (indolent (LG-NHL), n=63; aggressive (HG-NHL), n=61; mantle cell lymphoma (MCL), n=14) and Hodgkin's disease (HD, n=32). Median follow-up was 33 months (range, 12-82). The results show that frequencies were as follows: cumulative NRM at 3 years, 14%; acute and chronic graft-versus-host disease (GVHD) 35 and 52%, respectively; 3-year overall survival (OS), 69% for LG-NHL, 69% for HG-NHL, 45% for MCL and 32% for HD (P=0.058); and 3-year relapse incidence, 29, 31, 35 and 81%, respectively (P<0.001). Relapse risk differed significantly at 3 years between follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL) (14 versus 46%, P=0.04). Molecular remission occurred in 94 and 40% (P=0.002) of patients with FL and CLL, respectively. On multivariate analysis, OS was influenced by chemorefractory disease (hazard ratio (HR)=3.6), diagnosis of HD (HR=3.5), and acute GVHD (HR=5.9). RIC allogeneic SCT is a feasible and effective salvage strategy in both indolent and aggressive NHL.

Treatment of refractory chronic GVHD with rituximab: a GITMO study.

The anti-CD20 chimaeric monoclonal antibody Rituximab has recently been shown to induce significant clinical response in a proportion of patients with refractory chronic graft-versus-host disease (cGVHD). We now report 38 patients, median age 48 years (22-61), receiving Rituximab for refractory cGVHD, assessed for clinical response and survival. Median duration of cGVHD before Rituximab was 23 months (range 2-116), the median number of failed treatment lines was 3 (range 1 to > or =6) and the median follow-up after Rituximab was 11 months (1-88). Overall response rate was 65%: skin 17/20 (63%), mouth 10/21 (48%), eyes 6/14 (43%), liver 3/12 (25%), lung 3/8 (37.5%), joints 4/5, gut 3/4, thrombocytopaenia 2/3, vagina 0/2, pure red cell aplasia 0/1 and, myasthenia gravis 1/1. During the study period 8/38 died: causes of death were cGVHD progression (n=3), disease relapse (n=1), infection (n=3), sudden death (n=1). The actuarial 2 year survival is currently 76%. We confirm that Rituximab is effective in over 50% of patients with refractory cGVHD and may have a beneficial impact on survival.

Bone marrow failure associated with human herpesvirus 8 infection after transplantation.

BACKGROUND: Human herpesvirus 8 (HHV-8) infection has been linked to the development of Kaposi's sarcoma and to rare lymphoproliferative disorders. METHODS: We used molecular methods, serologic methods, in situ hybridization, and immunohistochemical analyses to study HHV-8 infection in association with nonmalignant illnesses in three patients after transplantation. RESULTS: Primary HHV-8 infections developed in two patients four months after each received a kidney from the same HHV-8-seropositive cadaveric donor. Seroconversion and viremia occurred coincidentally with disseminated Kaposi's sarcoma in one patient and with an acute syndrome of fever, splenomegaly, cytopenia, and marrow failure with plasmacytosis in the other patient. HHV-8 latent nuclear antigen was present in immature progenitor cells from the aplastic marrow of the latter patient. Identification of the highly variable K1 gene sequence of the HHV-8 genome in both the donor's peripheral-blood cells and the recipients' serum confirmed that transmission had occurred. HHV-8 viremia also occurred after autologous peripheral-blood stem-cell transplantation in an HHV-8-seropositive patient with non-Hodgkin's lymphoma. Reactivation of the infection was associated with the development of fever and marrow aplasia with plasmacytosis; there was no evidence of other infections. HHV-8 transcripts and latent nuclear antigen were expressed in the aplastic marrow but not in two normal marrow samples obtained before transplantation. CONCLUSIONS: Primary HHV-8 infection and reactivation of infection may be associated with nonneoplastic complications in immunosuppressed patients.

Nonmalignant disease associated with human herpesvirus 8 reactivation in patients who have undergone autologous peripheral blood stem cell transplantation.

Fever, cutaneous rash, and hepatitis-for which an infectious cause was suspected-developed in an Italian patient with non-Hodgkin lymphoma after autologous peripheral blood stem cell (PBSC) transplantation. Polymerase chain reaction (PCR) with degenerate primers for the highly conserved DNA polymerase gene of herpesviruses detected herpesvirus sequences 100% identical to human herpesvirus-8 (HHV-8) in serial cell-free serum samples, collected immediately before or concomitant with the occurrence of clinical symptoms; no other common infections were documented. The presence of the HHV-8 genome (clade C) was confirmed by PCR with HHV-8-specific primers for orf 26 and orf-K1. HHV-8 viremia was undetectable either before transplantation or when the patient was clinically asymptomatic. Semiquantitative PCR analysis showed variations of the viral load correlating with the clinical status. Anti-HHV-8 antibodies were detected before and after transplantation by an immunofluorescence assay for lytic antigens. Active HHV-8 infection may be associated with nonmalignant illness after PBSC/bone marrow transplantation.

Retrospective analysis of mantle cell lymphoma: experience of the "Gruppo Italiano per lo Studio dei Linfomi" (GISL).

BACKGROUND AND OBJECTIVE: Mantle cell lymphoma is a recently recognized histologic entity with specific biological and clinical features. Clinically, the reported unfavorable outcome of these patients has focused attention on this category of non-Hodgkin's lymphoma (NHL). DESIGN AND METHODS: The slide specimens of 69 NHL patients, originally classified as Working Formulation (WF) group B and E, were reviewed. The clinical features at presentation, response to therapy, response duration and survival were analyzed in cases reclassified as MCL. The correlation between clinical and histologic characteristics and the final outcome was evaluated. RESULTS: Out of 69 cases, 34 specimens were reclassified as MCL; in 6 patients, previously classified as WF group B, the nodular pattern was confirmed; in 2 instances the blastoid form was recognized. After a median follow-up of 35.7 months, the entire series displayed a median overall survival of 41.2 months; a significantly longer survival was associated with the nodular histologic pattern, IPI score < 2, response achievement, and a higher Hb level. The vast majority of patients received anthracycline-containing combination chemotherapy. Complete remission rate was 38.8% and overall response rate was 67.6%; response achievement was significantly influenced only by Hb level. Median response duration was 23.3 months. INTERPRETATION AND CONCLUSIONS: The present study confirms the unfavorable clinical course of MCL and the possible need for an alternative therapeutic strategy for this NHL category. Therefore, the correct identification of MCL at diagnosis appears of relevance.

Occurrence of a novel t(11;19)(q13;q13.3) in complete remission of acute promyelocytic leukemia.

A woman with t(15;17) and PML/RAR alpha positive acute promyelocytic leukemia (APL-M3v) achieved a complete remission (CR) with cytogenetic and molecular conversion, after one-month ATRA plus idarubicin treatment. During CR, less than one-month after consolidation therapy with topoisomerase II inhibitors, a novel t(11;19) (q13;q13.3) was detected in peripheral blood stem cells and later in harvest bone marrow cells. Persisting CR and the negativity for BCL1 and PRAD1 genes rearrangement, the autotransplantation was performed, with good outcome. The patient is still in CR eighteen months post-transplant, in spite of the persistence of a small t(11;19) clone in BM cells. The emergence of a novel chromosomal change during CR of acute leukemia is a rare phenomenon. This is the first t(11;19)(q13;q13.3) described in APL. This finding raises the issue of whether the abnormal karyotypes at remission might represent a risk of tumor recurrence. The meaning of this genomic instability is yet unknown.

[The treatment of the cardiac patient in dentistry and oromaxillofacial surgery. I. The practical management of patients with arrhythmias]. / Il trattamento del paziente cardiopatico in odontoiatria ed in chirurgia oro-maxillo-facciale. Nota 1: Management pratico nei pazienti portatori di turbe del ritmo.

Cardiac patients consist of a high incidence rate in odontostomatology, both clinical and surgical. Moreover this serious complication disease conditions odontostomatological and, particularly, surgical works. In this article the authors present the results of several years of research carried out to obtain a correct clinical and therapeutic approach for clinical and surgical dentistry. After an introduction on the clinical features of heart diseases the most important clinical cases of heart dysrhythmia are discussed: like, i.e. hypokinetic arrhythmia, hyperkinetic arrhythmia and the management of patients with pacemakers. The principal diacritic features of dysrhythmic diseases are illustrated. Anxiety is a sort of disease not directly related with dysrhythmia. Moreover a lot of clinical studies find in heart arrhythmia the principal problem caused by anxiety on heart physiology. Consequently the authors describe anxiety in the same part of pathologies commonly known as heart dysrhythmia. In the last phase the authors illustrate the most opportune therapeutic steps corresponding to the principal pathologies described above. These matters were dealt with from an odontostomatological point of view. The results obtained suggest the necessity of keeping to the management that was described. Actually a low percentage of accidents occurred only when the above-mentioned clinical processes were completely performed.

[The treatment of the cardiac patient in dentistry and oromaxillofacial surgery. II. The practical management of patients with hemodynamic pathologies]. / Il trattamento del paziente cardiopatico in odontoiatria ed in chirurgia oro-maxillo-facciale. Nota 2: Management pratico nei portatori di patologie emodinamiche.

When odontostomatological or surgical treatment is performed we suggest, in a first phase, to distinguish cardiac patients from the others. In a second phase a careful nosological diagnosis will be performed. Consequently, patients' medical history plays a fundamental role in both diagnostic phases. In this article the authors present the results of several years of research carried out to obtain a correct clinical and therapeutic approach for clinical and surgical Odontostomatology. After an introduction on the clinical features of heart hemodynamic pathologies the most important clinical cases are discussed: like, for example, acardiohemia, valvulopathies and heart decompensation. The principal diacritic features of hemodynamic diseases are illustrated. Essential hypertension (borderline and resident) is a sort of disease not directly related to hemodynamics pathology. Moreover a lot of clinical studies find in heart hemodynamic pathologies the principal problem caused by hypertension on heart physiology. Consequently the authors describe essential hypertension in the same part of pathologies commonly known as heart hemodynamic pathologies. In the last phase the authors illustrate the most opportune therapeutic steps corresponding to the principal pathologies above-described. These matters were dealt with from an odontostomatological point of view. The results obtained suggest the necessity of keeping to the management that was described. Actually a low percentage of accidents occurred only when the above-mentioned clinical processes were completely performed.

[Treatment of the patient with a coagulation defect in oral and maxillofacial surgery. III. The management of patients in a hypocoagulative state because of a hemophilic-type primary pathology]. / Il trattamento del paziente con difetto di coagulazione in chirurgia orale e maxillo-facciale. Nota III: Il management dei pazienti in stato ipocoagulativo a causa di una patologia primaria di tipo emofilico.

Hemophilia plays a particularly important role among the diseases caused by abnormal coagulation. Defective blood-clotting factor diseases have a particular importance between coagulopathies: hemophilia, among these hematic disorders, plays a principal role. In this paper the authors present the results of scientific research on hemophilic disease carried out to obtain a correct clinical and therapeutic approach for clinical and surgical Odontostomatology. The authors, after having presented in short the physiopathologic function of coagulation factors, illustrate the clinical and therapeutic aspects of Hemophilia A and Hemophilia B. The correct Odontostomatological and Maxillo-Facial Surgical approach is presented as the result of the authors' research. Also von Willebrand's disease is illustrated even if it is not exactly a hemophilic disease. This is because all hemophilias must produce a gynephoric inheritance pattern. Nevertheless clinical, therapeutic and molecular biology appearance suggests the illustration of von Willebrand's disease together with hemophilias. Von Willebrand's disease can be divided into three nosologic groups and to each one corresponds a particular clinical and therapeutic management. Such cases are illustrated and examined from an Odontostomatologic point of view. The results obtained suggest the necessity of keeping to the management that was described. Actually a low percentage of accidents occurred only when the above-mentioned clinical processes were completely performed.

[Management of facial pain resulting from cancer in oral and maxillofacial surgery]. / Il trattamento del dolore facciale di natura oncologica in chirurgia oro-maxillo-facciale.

Pain, which is among the most prevalent symptoms experienced by cancer patients, must absolutely be treated. The most important biologic effects of this sort of pain plays on patients' psychosociality. This is in reference to the quality of pain, the amount of pain and to the character of the patients. Actually, pain only in appearance is presented as a symptom; it is usually a disease. Patient assessment, the use of anticancer therapies and systematically administered non-opioid and opioid analgesics are pivotal. Practical aspects of cancer pain treatment include both drug selection, method of analgesic administration: selection of the appropriate route, dose titration and an understanding of the management of side effects. Pain therapy includes another series of possibilities like the use of adjuvant analgesics, psychological therapies, physiatric techniques and invasive interventions such as the use of intraspinal drugs, neural blockade and neuroablative techniques. This kind of therapy must be employed at all times, whether the case may be resolved surgically or not. So we think that pain can be effectively treated. This study was carried out to obtain the correct therapeutic approach for facial cancer pain syndrome. The research was performed on seven women and thirteen men with a mean age of 58 years. All the patients' clinical appearances were standardized with care. Study participants included odontostomatologists and anesthesiologists with experience of controlling cancer pain. The sensation of pain was quantified by means of the Visual Analogue Scale (VAS) while their psychosocial ability was assessed with the Karnofsky Performance Scale (KPS). In this way the authors hoped to obtain a good quality of standardization. The study was performed for a period of two months. The conclusions are that Trans Epidermis Nervous Stimulation (TENS) offers positive results for variable periods and only in 60% of patients with a low level of pain. The use of antiphlogistic non-steroid drugs and of opioid drugs, with a particular management requested from the personal clinical status of each patient, result as being the most effective therapeutic resource. Such therapies must be employed, whether the case may be resolved surgically or not. Nevertheless it is necessary to realize that drugs or other therapies for cancer pain are independent and propaedeutic to each surgical approach. Finally, the use of opioids is addressed in the management of patients with pain that is refractory to other interventions. This approach can provide adequate relief to the vast majority of patients. We find the morphinomania risk in cancer pain patients is not scientifically wellfounded.

[Management of patients with coagulation disorder in oral and maxillofacial surgery. I. Management of patients with hypocoagulation caused by primary thrombocytopathy]. / Il trattamento del paziente con difetto di coagulazione in chirurgia orale e maxillo-facciale. Nota II. Il management dei pazienti in stato ipocoagulativo a causa di una patologia primaria trombocitopatica.

Any oral and maxillo-facial surgical treatment, however urgent it may be, must not include pathological states in which the patient's life may be particularly at risk as, for example, with Disseminated Intravascular Coagulation (DIC) or throm-botic thrombocytopenic purpura. In this article the authors present the result of studies carried out on the nosology of thrombocytopathy from an odontostomatological point of view. Thrombocytopathy can be divided into two groups: the first including the pathologies with a predominant defective number of thrombocytes (i.e.: thrombocytopenia, thrombocythemia, thrombocyto-sis), the second including forms with predominant qualitative defects (commonly known as thrombocytopathies). The authors, after having presented in short the physiopathologic functions of thrombocytes, illustrate the clinical and therapeutic aspects of the most important thrombocytopathies. Morbus Maculosus Werhofii, Glanzmann's disease, Bernard-Soulier syndrome, thrombocytopathies from defective reaction of release, Thrombocytopathies from defective procoagulant activity of blood plaques, thrombocytopathies in linkage to other genetic anomalies, von Willebrand's pseudodisease and a lot of acquired thrombocytopathies are identified. In the last part the authors illustrate the most opportune clinical steps corresponding to the most important thrombocytopathies. The results obtained suggest the necessity of keeping to the management that was described, Actually a low percentage of accidents occurred only when the above-mentioned clinical processes were completely performed.