Rhs Liang

CD56 ˛ NK lymphomas: clinicopathological features and prognosis

The surface molecule CD56 marks a category of malignant lymphoma of putative natural killer (NK) cell origin. We conducted a retrospective analysis of 24 cases of CD56+ NK lymphoma/leukaemia to define the clinicopathologic and prognostic features of this specific group of lymphomas. 56 cases of nasal lymphomas and 204 cases with an initial diagnosis of peripheral T‐cell lymphoma were retrospectively analysed. To specifically examine lymphomas of putative NK origin, only those that were negative for surface expression of CD3 but positive for CD56 were analysed. 24 cases were identified. The initial predominant sites of involvement were nasal (n =18), palate (n = 1), nodal (n = 1) and multi‐organ (n =4). Clinically, in patients with disease localized to one anatomical site (n = 20), most had symptoms confined to the nose, with a high percentage in early stage (I: 91%; IV: 9%). The marrow was not involved in any of these cases. However, patients with multi‐organ involvement at presentation (n = 4) behaved differently. All presented acutely with pancytopenia, hepatosplenomegaly, and marrow infiltration with haemophagocytosis. A leukaemic phase was observed in one case. Anthracycline containing combination chemotherapy resulted in complete remission in 75% of patients with localized disease, but only in 25% with multi‐organ involvement. The median survival of patients with localized disease was 12 months, compared with 2 months in the multi‐organ group (P =0.06); the disease‐free survival was significantly better in the former (P <0.01). The overall median survival of all patients was still poor at 11 months.

Aldehyde dehydrogenase activity in leukemic blasts defines a subgroup of acute myeloid leukemia with adverse prognosis and superior NOD/SCID engrafting potential.

Aldehyde dehydrogenase (ALDH) activity is used to define normal hematopoietic stem cell (HSC), but its link to leukemic stem cells (LSC) in acute myeloid leukemia (AML) is currently unknown. We hypothesize that ALDH activity in AML might be correlated with the presence of LSC. Fifty-eight bone marrow (BM) samples were collected from AML (n=43), acute lymphoblastic leukemia (ALL) (n=8) and normal cases (n=7). In 14 AML cases, a high SSCloALDHbr cell population was identified (ALDH+AML) (median: 14.89%, range: 5.65–48.01%), with the majority of the SSCloALDHbr cells coexpressing CD34+. In another 29 cases, there was undetectable (n=23) or rare (⩽5%) (n=6) SSCloALDHbr population (ALDH−AML). Among other clinicopathologic variables, ALDH+AML was significantly associated with adverse cytogenetic abnormalities. CD34+ BM cells from ALDH+AML engrafted significantly better in NOD/SCID mice (ALDH+AML: injected bone 21.11±9.07%; uninjected bone 1.52±0.75% vs ALDH−AML: injected bone 1.77±1.66% (P=0.05); uninjected bone 0.23±0.23% (P=0.03)) with the engrafting cells showing molecular and cytogenetic aberrations identical to the original clones. Normal BM contained a small SSCloALDHbr population (median: 2.92%, range: 0.92–5.79%), but none of the ALL cases showed this fraction. In conclusion, SSCloALDHbr cells in ALDH+AML might denote primitive LSC and confer an inferior prognosis in patients.

Treatment outcome and prognostic factors for primary nasal lymphoma.

PURPOSE To report our experience managing a large series of Chinese patients with primary nasal lymphoma. PATIENTS AND METHODS From January 1975 to December 1993, 100 patients (median age, 50 years) with newly diagnosed primary nasal lymphoma were studied. There were four low-grade, 62 intermediate-grade, nine high-grade, and 25 unclassifiable lymphomas. Immunophenotyping was performed in 45 patients: eight B cell, 35 T cell, and two uncertain. All cases of angiocentric lymphoma that were typed were T cell. Fifty-two patients had stage I disease, 15 had stage II, four had stage III, and 29 had stage IV. Only 15 patients had B symptoms (weight loss, night sweats, and/or fever), and 11 had bulky disease. Thirty-nine patients with clinically localized stage I and II disease received local radiotherapy alone (before 1980), and the remaining 28 stage I and II patients received combination chemotherapy followed by local radiotherapy. The 33 patients with advanced stage III and IV disease were given combination chemotherapy, and additional radiotherapy was given to five of them who had bulky local disease. RESULTS Significantly higher complete remission rates were observed in patients with early stages of disease and those without B symptoms. Superior disease-free survival after complete remission was observed in patients with stage I/II disease. Univariate factors associated with a better overall survival included age less than 60 years, stage I disease, and absence of B symptoms. Survival was significantly better in the subgroup of patients with stage I disease. CONCLUSION Patients with nasal lymphoma, especially those with advanced disease, seemed to have a poor prognosis, and their clinical outcome was not improved significantly by the use of chemotherapy instead of radiotherapy or the use of doxorubicin-containing chemotherapeutic regimens.

A prospective study of symptomatic bacteremia following platelet transfusion and of its management

BACKGROUND: The danger of bacteremia due to contaminated platelets is not well known. There are also no established guidelines for the management of febrile reactions after platelet transfusion.

Human herpesvirus 6 and human herpesvirus 7 infections in bone marrow transplant recipients

Human cytomegalovirus (HCMV), human herpesvirus‐6 (HHV‐6), and human herpesvirus‐7 (HHV‐7) DNA in peripheral blood leukocytes (PBL) of 61 bone marrow transplant recipients was monitored weekly during the first 12 weeks post‐transplantation by a nested polymerase chain reaction (PCR). Thirty‐seven (61%), 17 (28%), and 32 (53%) of patients had one or more PBL specimens positive for HCMV, HHV‐6 or HHV‐7 DNA, respectively. HHV‐7 DNA in PBL during the early post‐transplant period was associated with a longer time to neutrophil engraftment (mean 28.8 days vs 19.8 days; P = 0.01). In two patients who failed to engraft, HHV‐6 DNA and HHV‐7 DNA was detected in plasma and PBL, respectively, early in their post‐transplant period. Patients with HCMV disease were more likely to have concurrent HHV‐7 DNA in PBL prior to onset of disease than were patients with asymptomatic HCMV infection, suggesting that HHV‐7 may be a cofactor in the progression from HCMV infection to HCMV disease. In the 17 patients (179 specimens) in whom viral DNA in plasma was studied (in addition to PBL), a positive result was found only in 3. In each, viral DNA in plasma appeared to correlate with clinically significant disease. HHV‐7 DNA in plasma was associated with encephalitis in an allograft recipient. J. Med. Virol. 53:295–305, 1997.

Methylation of p15 and p16 Genes in Acute Promyelocytic Leukemia: Potential Diagnostic and Prognostic Significance

PURPOSE To investigate the frequency of p15 and p16 gene promoter methylation in acute promyelocytic leukemia (APL), and to define its value in the detection of minimal residual disease (MRD) and treatment prognostication. PATIENTS AND METHODS Bone marrow DNA obtained from 26 patients with APL at diagnosis and during follow-up was studied with the methylation-specific polymerase chain reaction (MS-PCR). Serial marrow DNA was studied by MS-PCR for MRD, and disease-free and overall survival were correlated with p15 methylation status at diagnosis. RESULTS MS-PCR for p16 and p15 gene methylation has a maximum sensitivity of 10(-4) and 10(-5). At diagnosis, 19 patients (73.1%) exhibited p15 methylation, whereas only three patients (11.5%) exhibited p16 methylation, all of whom had concomitant p15 methylation. During follow-up, p16 methylation was acquired in two patients, one during the third hematologic relapse, and the other during transformation into therapy-related myelodysplastic syndrome. Six patients were evaluated serially with MS-PCR for p15 methylation at diagnosis and at follow-up examinations. Persistent p15 methylation preceded subsequent hematologic relapses in two patients, and conversion to negative MS-PCR for p15 methylation correlated with prolonged survival in another four patients. The 5-year disease-free survival of patients with p15 methylation was significantly inferior to that of patients without p15 methylation (15% v 62.5%; P =.02), and this remained significant in multivariate analysis. CONCLUSION In APL, p15 but not p16 gene methylation is frequent. It is possible that p16 methylation is acquired during clonal evolution. p15 methylation is a potential marker of MRD and might be of prognostic significance.

Epigenetic dysregulation of Wnt signaling pathway in multiple myeloma

Wnt signaling has recently been implicated in carcinogenesis. We studied the activity of Wnt signaling and the methylation status of WIF1, DKK3, APC, SFRP1, SFRP2, SFRP4 and SFRP5 by methylation-specific PCR in myeloma cell lines and primary myeloma samples. Of the four cell lines, Wnt signaling was constitutively activated in LP1 and WL2, correlating with hypermethylation and hence silencing. Moreover, 5-aza-2′-deoxycytidine treatment of these two cell lines showed progressive demethylation of methylated Wnt inhibitors, re-expression of transcripts and downregulation of Wnt signaling. In both LP1 and WL2 cells, multiple Wnts and Fzs were simultaneously expressed. Treatment of WL2, in which SFRP1 was completely methylated, with recombinant secreted Frizzled-related protein 1 (SFRP1) induced downregulation of Wnt signaling and inhibition of proliferation. In primary myeloma samples, 42% patients had methylation of at least one of these seven genes, of which 61.9% had ⩾2 genes methylated. In conclusion, Wnt signaling is constitutively activated in myeloma, associated with methylation silencing of one or multiple soluble Wnt antagonists. An autocrine loop regulating Wnt signaling was demonstrated in the myeloma plasma cells, in which cellular proliferation was efficiently inhibited by recombinant SFRP1. Methylation study of a panel of genes, regulating a cellular pathway instead of isolated genes, is important.

Clinicopathological features and risk factors of clinically overt haemorrhagic cystitis complicating bone marrow transplantation.

Haemorrhagic cystitis (HC) is an important complication after bone marrow transplantation (BMT). Overt HC (grade ⩾2, gross haematuria, clot retention and impairment of renal function), clinically more important than mild and occult HC (grade 1, microscopic haematuria), leads to substantial morbidity and occasional mortality. We retrospectively analyzed 32 cases of clinically overt HC from a series of 236 BMT patients. Significant risk factors included the use of busulphan during conditioning, allogeneic BMT and acute GVHD. Logistic regression showed GVHD to be the most important risk factor. According to the time of engraftment, HC could be divided into pre- and post-engraftment subtypes. Pre-engraftment HC was brief, not more severe than grade 2, and subsided with supportive treatment. In contrast, post-engraftment HC was protracted, often of grade ⩾3, associated with severe GVHD, and required surgical intervention in many cases. Polyoma BK viruria, but not adenoviruria, could be demonstrated in both types of HC. The increased severity and association with GVHD of post-engraftment HC suggested that attack of urothelium by immunocompetent cells, possibly directed against BK viral antigens, might play a pathogenetic role.Bone Marrow Transplantation (2002) 29, 509–513. doi:10.1038/sj.bmt.1703415

Autologous bone marrow transplantation for primary nasal T/NK cell lymphoma

Primary nasal T or NK cell lymphoma is rarely seen in the Western population but is more common in the Orientals. Although it often presents with localized disease, the prognosis is generally poor. Long-term remission is seen in only 50% of patients with stage I disease despite aggressive treatment with chemotherapy and radiotherapy, and is invariably fatal if disseminated. Conventional chemotherapy for relapsed disease is usually not successful. Since 1992, three patients with relapsed primary nasal T/NK cell lymphoma have received high-dose chemotherapy with autologous bone marrow rescue at Queen Mary Hospital, Hong Kong. High-dose cyclophosphamide, BCNU and etoposide were used for conditioning. Two of them had a favourable response and remained in complete remission at 12 and 44 months post-transplant. The third patient unfortunately had a systemic relapse 6 months after the transplant. It appears from this experience that, like other aggressive non-Hodgkin’s lymphomas, high-dose chemotherapy and autologous bone marrow rescue is an effective treatment for relapsed primary nasal lymphoma following failure of conventional chemotherapy and radiotherapy.

Combined arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia recurring from previous relapses successfully treated using arsenic trioxide.

Summary.  The optimal treatment of acute promyelocytic leukaemia (APL) recurring from relapses successfully treated using arsenic trioxide (As2O3) is undefined. Three APL patients relapsing from As2O3‐induced remission were studied. Re‐treatment with As2O3 failed in one patient in third relapse, and resulted in morphological but not molecular remission in another patient. Combination therapy with As2O3 and all‐trans retinoic acid (ATRA), however, resulted in morphological and molecular remission in all three cases, with a follow‐up time ranging from 6 to 16 months. Our results suggest a synergistic therapeutic effect between As2O3 and ATRA in APL in advanced relapse.