Risk of non-Hodgkin's lymphoma following tuberculosis

To study the association between chronic infections and non-Hodgkin's lymphoma (NHL), we assessed the risk of NHL in a Swedish cohort of 5050 individuals with tuberculosis 1939-1960. The overall relative risk was moderately increased, largely accounted for by high risks following severe tuberculosis diagnosed a long time ago.     

BRAF mutations in non-Hodgkin's lymphoma

Ras proteins control signalling pathways that are key regulators of several aspects of normal cell growth and malignant transformation. BRAF, which encodes an RAF family member in the downstream pathway of RAS, is somatically mutated in a number of human cancers. The activating mutation of BRAF is known to play a role in tumour development. As there have been no data on the BRAF mutation in non-Hodgkin's lymphoma (NHL), we analysed the genomic DNAs from 164 NHLs by polymerase chain reaction (PCR)-based single-strand conformation polymorphism (SSCP) for the detection of somatic mutations of BRAF (exons 11 and 15). Overall, we detected BRAF mutations in four NHLs (2.4%). Whereas most BRAF mutations in human cancers involved V599 of BRAF, all of the four BRAF mutations in the NHLs involved other amino acids (one G468A, two G468R and one D593G). To our knowledge, this is the first report on BRAF mutation in NHL, and the data indicate that BRAF is occasionally mutated in NHL, and suggest that BRAF mutation may contribute to the tumour development in some NHLs.     

Long-term follow-up of patients treated with radiotherapy alone for early-stage histologically aggressive non-Hodgkin's lymphoma

Historically localised aggressive non-Hodgkin's lymphoma (NHL) has been treated with involved field radiotherapy (RT), chemotherapy, or a combination of both modalities. The current weight of evidence supports a preference for combined modality treatment (CMT). Increased patient age at diagnosis is well recognised as a poor prognostic indicator in NHL, but despite this some perceive CMT as too toxic for use in the elderly. As a result, some older patients continue to be offered RT alone. Here, we present long-term follow-up of 377 adults of all ages treated with RT alone for early-stage diffuse large-cell lymphoma on British National Lymphoma Investigation trials between 1974 and 1997. 10-year cause-specific survival in patients older than 60 years was poor and significantly inferior to that in younger patients (47 and 75% respectively; P<0.001). There is growing evidence that short-course chemotherapy, with or without RT, is superior to RT alone in early-stage aggressive NHL, in elderly as well as in younger patients. Increased age alone should not exclude patients from systemic treatment for early-stage aggressive NHL.     

Comparison of the distribution of non-AIDS Kaposi's sarcoma and non-Hodgkin's lymphoma in Europe.

To evaluate whether some form of mild immunosuppression may influence the geographical distribution of non-AIDS Kaposi's sarcoma (KS), we correlated incidence rates of KS and non-Hodgkin's lymphoma in individuals aged 60 or more in 18 European countries and Israel. Significant positive correlations emerged but, within highest risk countries (i.e. Italy and Israel), internal correlations were inconsistent.     

Second primary cancers in patients with gastric cancer

Background

The risk of developing a second primary tumour in patients with gastric carcinoma is higher than among the general population. The aim was to investigate the clinicopathological characteristics of the second primary cancers in patients with gastric cancer in this study.

Patients and methods

In the retrospective study, patients with gastric cancers were evaluated between 1995 and 2005 for primary tumours according to Warren and Gates’ criteria related with the second primary cancers.

Results

Nine of the 112 patients with gastric cancer had second primary cancers. Seven of the patients were males and two females. Six patients with gastric cancers had synchronous, and three had metachronous tumours. The age of the patients ranged from 53 to 78 years, and the mean age was 61 ± 8.3 years. The most frequent site of occurrence of the second tumours was the colo-rectum (33%) followed by the upper respiratory system (22%), and the urogenital system (22%) in descending order of frequency.

Conclusions

The incidence of the second primary cancer in gastric cancer patients was 8% in the current report. It is recommended that careful preoperative and postoperative examinations for other primary cancers, as well as for the extent of the primary gastric carcinoma, are carried out. Because colorectal cancer was the most common carcinoma combined with gastric carcinoma, the surveillance for this carcinoma (e.g., colonoscopy, abdominopelvic CT) would be appropriate after the diagnosis of gastric carcinoma.     

A phase II trial of bryostatin 1 in patients with non-Hodgkin's lymphoma

Bryostatin 1 is a naturally occurring macrocyclic lactone with promising antitumour and immunomodulatory function in preclinical and phase I clinical investigations. In this phase II study, 17 patients with progressive non-Hodgkin's lymphoma of indolent type (NHL), previously treated with chemotherapy, received a median of 6 (range 1-9) intravenous infusions of 25 microg/m(2) bryostatin 1 given once weekly over 24 hours. In 14 evaluable patients no responses were seen. Stable disease was attained in one patient for 9 months. The principal toxicities were myalgia and phlebitis. Treatment was discontinued early because of toxicity alone (phlebitis) in 2 patients, toxicity in addition to progressive disease in 3 patients (myalgia and phlebitis n = 2; thrombocytopenia n = 1) and progressive disease in 5 patients. The results fail to demonstrate efficacy of this regimen of bryostatin 1 in the treatment of NHL. In light of preclinical data that demonstrate synergy between bryostatin 1 and several cytotoxic agents and cytokines, clinical studies to investigate bryostatin 1 in combination are warranted. We also present data to demonstrate that central venous lines may be used in future studies to avoid phlebitis.     

Malignant large-cell non-Hodgkin's lymphoma of the spleen

Primary malignant tumours of the spleen are rare, with non-Hodgkin's lymphoma being the most common. A case of malignant large-cell lymphoma of the spleen in a patient with unexplained splenomegaly, is presented. There are very few previous reports on this condition in the radiological literature. The sonographic, computed tomographic and angiographic findings are described, with a brief review of the literature on this condition. Although there are no specific radiological findings to diagnose this condition, it has to be considered in the differential diagnosis of a solitary lesion in the spleen.     

Hepatitis C virus and non-Hodgkin's lymphoma: Findings from the Swiss HIV Cohort Study

Infections with hepatitis C virus (HCV) and, possibly, hepatitis B virus (HBV) are associated with an increased risk of non-Hodgkin's lymphoma (NHL) in the general population, but little information is available on the relationship between hepatitis viruses and NHL among people with HIV (PHIV). We conducted a matched case-control study nested in the Swiss HIV Cohort Study (SHCS). Two hundred and ninety-eight NHL cases and 889 control subjects were matched by SHCS centre, gender, age group, CD4+ count at enrollment, and length of follow-up. Odds ratios (OR) and corresponding 95% confidence intervals (CI) were computed using logistic regression to evaluate the association between NHL and seropositivity for antibodies against HCV (anti-HCV) and hepatitis B core antigen (anti-HBc), and for hepatitis B surface antigen (HBsAg). Anti-HCV was not associated with increased NHL risk overall (OR = 1.05; 95% CI: 0.63-1.75), or in different strata of CD4+ count, age or gender. Only among men having sex with men was an association with anti-HCV found (OR = 2.37; 95% CI: 1.03-5.43). No relationships between NHL risk and anti-HBc or HBsAg emerged. Coinfection with HIV and HCV or HBV did not increase NHL risk compared to HIV alone in the SHCS.     

Survival in patients with intermediate or high grade non-Hodgkin's lymphoma: meta-analysis of randomized studies comparing third generation regimens with CHOP

In patients with intermediate or high grade non-Hodgkin lymphoma (NHL), third generation chemotherapy regimens have been introduced to improve survival in comparison with the standard CHOP regimen. However, most studies have found no difference between these two treatments. We conducted a meta-analysis to assess the effectiveness of third generation regimens as compared with CHOP. Our study included the randomized controlled trials published in English from 1970 to 1999. After a Medline search, 5 trials were found to meet our inclusion criteria. A total of 1982 patients, that were enrolled in these trials, were included in the survival meta-analysis. Our methodology retrieved patient-level information from all of these subjects; survival up to 9 years after randomization was compared between the two treatment options. The results of our meta-analysis showed that, in comparison with CHOP, third generation chemotherapy did not prolong survival at levels of statistical significance (chi-square by log-rank test = 1.44, P = 0.23). The relative death risk for third generation regimens vs. CHOP was 0.92 (95%CI: 0.80 to 1.06;P = 0.26). We conclude that, on the basis of our meta-analysis, third generation regimens do not confer any survival benefit to patients with intermediate or high grade NHL as compared with CHOP.     

Loss of chromosome 11q21-23.1 and 17p and gain of chromosome 6p are independent prognostic indicators in B-cell non-Hodgkin's lymphoma.

Comparative genomic hybridization (CGH) was employed to study chromosomal aberrations in relation to cell proliferation, apoptosis, and patient survival in 94 cases of B-cell non-Hodgkin's lymphoma diagnosed between 1983 and 1993. Eighty cases had aberrations by CGH. Chromosomal regions 1p21-31.1 (10%), 6cen-q24 (12%), 8p (11%), 9p21-ter (14%), 11q21-23.1 (11%), 13q13-21.1 (12%), and 17p (15%) were frequently lost. Gains were found at 3q21-ter (22%), 6p (11%), 7p (12%), 8q23-ter (13%), 12cen-q15 (17%), 17q24-ter (13%), and 18q13.3-21 (20%). A high number of aberrations (> or = 4, 33 cases) was associated (P < or = 0.001) with the mantle cell and diffuse large B-cell lymphoma subtypes, a high fraction of tumour cells in S phase, and short survival (RR (relative risk) = 3.7). Loss of 1p21-31.1, 8p, 9p21-ter, 11q21-23.1, and 13q13-21.1 were associated with mantle cell lymphoma (P < or = 0.03), while gain of 6p and 12cen-q15 were more frequent in diffuse large B-cell and small lymphocytic lymphoma, respectively (P = 0.04). Loss of 8p and 17p, and gain of 3q21-ter, 6p, 7p, and 8q23-ter were associated with a high S phase fraction (P < or = 0.03), but none of the aberrations were associated with tumour apoptotic fraction (P > or = 0.13). The most important prognostic CGH parameters (P < 0.001) were losses of 11q21-23.1 (RR = 3.8) and 17p (RR = 4.4), and gain of 6p (RR = 4.2). The latter parameters and IPI were the only ones with independent prognostic value (RR = 10, 5.0, 6.7, and 3.7, respectively; P < 0.001) when assessed together with lymphoma sub-type, primary versus relapse cases, treatment, B symptoms, S phase fraction, and presence of BCL1 and BCL2 translocations. A combined CGH/IPI binary parameter had high prognostic value for patients receiving different treatments, with various lymphoma sub-types, and for primary as well as relapse cases.     

A phase III trial comparing CHOP to PMitCEBO with or without G-CSF in patients aged 60 plus with aggressive non-Hodgkin's lymphoma

The management of older patients with aggressive non-Hodgkin's lymphoma presents a challenge to the physician. Age is a poor prognostic indicator, due to reduced ability to tolerate and maintain dose-intensive chemotherapy. Generally, older patients demonstrate a lower response rate, reduced survival and increased toxicity, although the majority of large randomised trials exclude older patients. This randomised trial was conducted in patients 60 years or over to compare CHOP (cyclophosphamide 750 mg m(-2), doxorubicin 50 mg m(-2), vincristine 1.4 mg m(-2), prednisolone 100 mg) with PMitCEBO (mitoxantrone 7 mg m(-2), cyclophosphamide 300 mg m(-2), etoposide 150 mg m(-2), vincristine 1.4 mg m(-2), bleomycin 10 mg m(-2) and prednisolone 50 mg). Due to the myelosuppressive nature of these regimens, patients were also randomised to the addition of G-CSF. The formal results of this trial with long-term follow-up are now reported. Data were analysed to assess efficacy and toxicity. Overall response rate was 84% in the CHOP arm and 83% in the PMitCEBO arm, with overall response rates of 83% for the use of G-CSF and 84% for no G-CSF. At median 44 months follow-up, there was no significant difference in failure-free, progression-free or overall survival between the CHOP and PMitCEBO arms. At 3 years, the actuarial failure-free survival was 44% in CHOP recipients and 42% in PMitCEBO recipients and the 3-year actuarial overall survival was 46% and 45% respectively. There was no significant difference in the failure-free, progression-free or overall survival with the addition of G-CSF.     

Patterns of mortality after prolonged follow-up of a randomised controlled trial using granulocyte colony-stimulating factor to maintain chemotherapy dose intensity in non-Hodgkin's lymphoma

The effect of utilising granulocyte colony-stimulating factor (G-CSF) to maintain chemotherapy dose intensity in non-Hodgkin's lymphoma (NHL) on long-term mortality patterns has not been formally evaluated. We analysed prolonged follow-up data from the first randomised controlled trial investigating this approach. Data on 10-year overall survival (OS), progression-free survival (PFS), freedom from progression (FFP) and incidence of second malignancies were collected for 80 patients with aggressive subtypes of NHL, who had been randomised to receive either VAPEC-B chemotherapy or VAPEC-B+G-CSF. Median follow-up was 15.7 years for surviving patients. No significant differences were found in PFS or OS. However, 10-year FFP was better in the G-CSF arm (68 vs 47%, P=0.037). Eleven deaths from causes unrelated to NHL or its treatment occurred in the G-CSF arm compared to five in controls. More deaths occurred from second malignancies (4 vs 2) and cardiovascular causes (5 vs 0) in the G-CSF arm. Although this pharmacovigilance study has insufficient statistical power to draw conclusions and is limited by the lack of data on smoking history and other cardiovascular risk factors, these unique long-term outcome data generate hypotheses that warrant further investigation.     

Second primary cancers in breast cancer patients in Slovenia

Data from the Cancer Registry of Slovenia were used in a cohort studyto determine whether the incidence of second primary cancers in patients withfirst primary breast cancer differs from the incidence expected in thegeneral population. Special interest was given to long-term survivors. Theexpected numbers of second primary cancers were calculated by multiplying thenumber of appropriate person-years at risk by the corresponding age-andcalendar-period-specific cancer incidence rates for women in Slovenia. Therisk of a second primary cancer was expressed as the standardized incidenceratio (SIR). Of the 8,917 patients newly diagnosed in the period 1961-85 andfollowed-up to the end of 1994, 547 (6.2 percent) developed second primarycancers, whereas 410 (4.7 percent) were expected (SIR = 1.3, 95 percentconfidence interval [CI] = 1.2-1.4). The risk was higher among youngerpatients. In long-term survivors, the risk was increased significantly forsecond primary cancer of th e breast (SIR = 1.4, CI = 1.1-1.7), lung cancer(SIR = 1.6, CI = 1.1-2.3), melanoma (SIR = 2.7, CI = 1.5-4.4) andnon-melanoma skin cancers (SIR = 2.0, CI = 1.6-2.4), corpus uteri cancer (SIR= 1.6, CI = 1.2-2.1), ovarian cancer (SIR = 2.3, CI = 1.7-3.0), and thyroidcancer (SIR = 2.5, CI = 1.2-4.6). Our results confirm the findings of severalcohort studies carried out in Europe, the United States, and Japan,indicating that breast cancer patients should be monitored carefully for theoccurrence of second primary cancers.     

Second primary malignancies after treatment for malignant lymphoma

To determine the incidence and possible causes of second primary malignancies after treatment for Hodgkin's and Non-Hodgkin's lymphoma (HL and NHL). A cohort of 3764 consecutive patients diagnosed with HL or NHL between January 1970 and July 2001 was identified using the Sheffield Lymphoma Group database. A search was undertaken for all patients diagnosed with a subsequent primary malignancy. Two matched controls were identified for each case. Odds ratios were calculated to detect and quantify any risk factors in the cases compared to their matched controls. Mean follow-up for the cohort was 5.2 years. A total of 68 patients who developed second cancers at least 6 months after their primary diagnosis were identified, giving a crude incidence of 1.89% overall: 3.21% among the patients treated for HL, 1.32% in those treated for NHL. Most common were bronchial, breast, colorectal and haematological malignancies. High stage at diagnosis almost reached statistical significance in the analysis of just the NHL patients (odds ratio = 3.48; P = 0.068) after adjustment for other factors. Treatment modality was not statistically significant in any analysis. High stage at diagnosis of NHL may be a risk factor for developing a second primary cancer.     

Pathologic fracture after radiation therapy for primary non-Hodgkin's malignant lymphoma of bone

Between 1963 and 1981, 32 patients with biopsy proven non-Hodgkin's lymphoma involving bone were treated at the Mallinckrodt Institute of Radiology either with radiation alone or in conjunction with chemotherapy. An unexpectedly high rate of fracture at the site of the tumor was observed. Six patients were excluded because they survived less than six months after the completion of radiotherapy or were lost to follow-up within six months. There were 15 appendicular and 17 axial sites treated. Local control was achieved in 30 of 32. There were 10 patients with appendicular lesions of which seven suffered a fracture. Of the seven patients with lesions in a weight bearing bone, six suffered fractures. Twenty-six sites of involvement received less than 5000 rad. Five sites of involvement with diffuse histiocytic lymphoma (DHL) involving the appendicular skeleton received 5000 to 6000 rad. One site with DHL involving the axial skeleton received 5000 rad. Of the six patients receiving high dose, two presented with pathologic fractures of the femur requiring surgical stabilization and the remaining four patients suffered subsequent fractures 7 to 30 months after completion of therapy. Two of these six had local recurrence of disease. It appears that involvement of the appendicular skeleton by lymphoma frequently results in fracture. Doses of 5000 rad or greater do not increase the probability of local control but may contribute to the risk of fracture following radiotherapy.     

Methylation of miR-155-3p in mantle cell lymphoma and other non-Hodgkin's lymphomas

Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin''s lymphoma (NHL). In cancers, tumor suppressive microRNAs may be silenced by DNA hypermethylation. By microRNA profiling of representative EBV-negative MCL cell lines before and after demethylation treatment, miR-155-3p was found significantly restored. Methylation-specific PCR, verified by pyrosequencing, showed complete methylation of miR-155-3p in one MCL cell line (REC-1). 5-aza-2′-deoxycytidine treatment of REC-1 led to demethylation and re-expression of miR-155-3p. Over-expression of miR-155-3p led to increased sub-G1 apoptotic cells and reduced cellular viability, demonstrating its tumor suppressive properties. By luciferase assay, lymphotoxin-beta (LT-β) was validated as a miR-155-3p target. In 31 primary MCL, miR-155-3p was found hypermethylated in 6(19%) cases. To test if methylation of miR-155-3p was MCL-specific, miR-155-3p methylation was tested in an additional 191 B-cell, T-cell and NK-cell NHLs, yielding miR-155-3p methylation in 66(34.6%) including 36(27%) non-MCL B-cell, 24(53%) T-cell and 6(46%) of NK-cell lymphoma. Moreover, in 72 primary NHL samples with RNA, miR-155-3p methylation correlated with miR-155-3p downregulation (p = 0.024), and LT-β upregulation (p = 0.043). Collectively, miR-155-3p is a potential tumor suppressive microRNA hypermethylated in MCL and other NHL subtypes. As miR-155-3p targets LT-β, which is an upstream activator of the non-canonical NF-kB signaling, miR-155-3p methylation is potentially important in lymphomagenesis.     

Risk of lymphoma subtypes after solid organ transplantation in the United States

Background:

Solid organ transplant recipients have high risk of lymphomas, including non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). A gap in our understanding of post-transplant lymphomas involves the spectrum and associated risks of their many histologic subtypes.

Methods:

We linked nationwide data on solid organ transplants from the US Scientific Registry of Transplant Recipients (1987–2008) to 14 state and regional cancer registries, yielding 791 281 person-years of follow-up for 19 distinct NHL subtypes and HL. We calculated standardised incidence ratios (SIRs) and used Poisson regression to compare SIRs by recipient age, transplanted organ, and time since transplantation.

Results:

The risk varied widely across subtypes, with strong elevations (SIRs 10–100) for hepatosplenic T-cell lymphoma, Burkitt''s lymphoma, NK/T-cell lymphoma, diffuse large B-cell lymphoma, and anaplastic large-cell lymphoma (both systemic and primary cutaneous forms). Moderate elevations (SIRs 2–4) were observed for HL and lymphoplasmacytic, peripheral T-cell, and marginal zone lymphomas, but SIRs for indolent lymphoma subtypes were not elevated. Generally, SIRs were highest for younger recipients (<20 years) and those receiving organs other than kidneys.

Conclusion:

Transplant recipients experience markedly elevated risk of a distinct spectrum of lymphoma subtypes. These findings support the aetiologic relevance of immunosuppression for certain subtypes and underscore the importance of detailed haematopathologic workup for transplant recipients with suspected lymphoma.     

Follicular non-Hodgkin's lymphoma in Hong Kong Chinese: a retrospective analysis

Follicular lymphoma is relatively rare in Hong Kong Chinese. Fifty-two patients with follicular lymphoma were reviewed. The histology was nodular lymphocytic poorly differentiated (NLPD) in 75 per cent, nodular mixed (NM) in 21 per cent and nodular histiocytic (NH) in 4 per cent. Our patients appeared to have a higher proportion of NLPD and a lower proportion of NM lymphoma than the western series. Fifty patients were analysed excluding the two patients with NH lymphoma. They had a median age of 50 and a male to female ratio of 0.92. Seventy-two per cent of them presented with asymptomatic lymph node enlargement. Twenty per cent had B symptoms and 32 per cent bulky tumour. Twelve per cent had stage I disease, 2 per cent stage II, 30 per cent stage III and 56 per cent stage IV. A high incidence of bone marrow involvement (48 per cent of all patients) was found. All seven stage I-II patients responded to involved-field radiotherapy alone and none of them has relapsed. The 43 stage III-IV patients were treated with chemotherapy without deferral and a majority of them received CVP (51.1 per cent) or chlorambucil alone (34.9 per cent). The complete response rate of stage III-IV patients was 81 per cent and 26 per cent of the complete responders relapsed. The 5-years disease-free survival (DFS) and overall survival of all patients (stage III and IV) were 50 per cent and 65 per cent respectively. The DFS curve showed a pattern of continuous relapses. Stage III patients appeared to have a better complete response rate, a lower relapse rate and superior disease-free survival than stage IV patients but the differences did not reach statistical significance. However, the overall survival of stage III patients was significantly better than stage IV patients (p less than 0.02). Other factors including sex, age, presence of bulky tumour, B symptoms, histologic subtypes and the chemotherapeutic regimes did not significantly affect their prognosis.     

Treatment of non-Hodgkin's lymphoma in the elderly: an update

Recent studies specifically directed toward assessing the outcome of older patients with non-Hodgkin's lymphoma (NHL) indicate that age per se is an important and independent prognostic factor for response and survival. We report a review of the clinical trials of the literature and the Aviano Group experience in the treatment of NHL in the elderly. Prospective studies have addressed therapeutic approaches in these patients. Direct comparison of trial results is difficult since different age limits were set for the inclusion of patients under study. These studies suggest that older patients with aggressive NHL should be treated with curative intent. Copyright © 1998 John Wiley & Sons, Ltd.