Cancer risks among relatives of children with Hodgkin and non-Hodgkin lymphoma

A role for genetic susceptibility in the aetiology of childhood lymphomas was investigated in 454 families of children with histologically confirmed Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) from Northwest England. Cancers in parents were obtained from the UK National Health Service Central Register and in other close relatives by interview with the parents. The cancer incidence among relatives was compared with expected incidence based on cancer registry data for England. There were 197 cancers in relatives (SIR 1.0 95% CI 0.8-1.1). In families of children with HL, there was an excess of HL in the first degree relatives (SIR 5.8 95% CI 1.2-16.9). Excesses of HL diagnosed under population median age (SIR 4.1 95% CI 1.1-10.6) were seen among all relatives and relatives of children who were below the median age at diagnosis (SIR 5.5 95% CI 1.1-16.0). In families of children with NHL, there were non-significant excesses of central nervous system (CNS) tumours in the first degree relatives (SIR 2.9 95% CI 0.8-7.4) and in the second and third degree relatives (SIR 1.5). There were significant excesses of CNS tumours diagnosed under the population median age (SIR 2.8 95% CI 1.1-5.8) in all relatives. Excess CNS tumours were also seen among relatives of children below the median age at diagnosis (SIR 3.2 95% CI 1.1-7.6). In conclusion, genetic susceptibility in some families of children with lymphoma might be operating, but aetiologies in HL and NHL appear to be different. Possible interpretations of our findings, in the context of putative genetic and infectious aetiologies, are discussed.     

Pulmonary tuberculosis increases the risk of lung cancer: a population-based cohort study

BACKGROUND:

The possible effect of pulmonary tuberculosis (TB) on subsequent lung cancer development has been suspected, but the evidence remains inconsistent. The purpose of this study was to perform a nationwide population‐based cohort study to investigate the risk of lung cancer after pulmonary TB infection.

METHODS:

This nationwide population‐based cohort study was based on data obtained from the Taiwan National Health Insurance Database. In total, 5657 TB patients and 23,984 controls matched for age and sex were recruited for the study from 1997 to 2008.

RESULTS:

The incidence rate of lung cancer (269 of 100,000 person‐years) was significantly higher in the pulmonary TB patients than that in controls (153 of 100,000 person‐years) (incidence rate ratio [IRR], 1.76; 95% confidence interval [CI], 1.33‐2.32; P < .001). Compared with the controls, the IRRs of lung cancer in the TB cohort were 1.98 at 2 to 4 years, 1.42 at 5 to 7 years, and 1.59 at 8 to 12 years after TB infections. The multivariate Cox proportional hazards model revealed pulmonary TB infections (hazard ratio [HR], 1.64; 95% CI, 1.24‐2.15; P < .001) and chronic obstructive pulmonary disease (HR, 1.09; 95% CI, 1.03‐1.14; P = .002) to be independent risk factors for lung cancer.

CONCLUSIONS:

Pulmonary infection with TB is associated with an increased risk of lung cancer. Cancer 2011. © 2010 American Cancer Society.     

Management of breast cancer after Hodgkin’s lymphoma and paediatric cancer

RationaleThe risk of women developing a breast cancer (BC) after receiving chest radiotherapy for paediatric cancers and Hodgkin lymphomas is well established. The aim of this study was to assess these patients’ clinical characteristics and clinical outcomes.MethodsThe study concerns women with a history of primary neoplasms treated with chest irradiation ± chemotherapy and subsequently diagnosed with BC.ResultsWe identified 78 women who developed BC (invasive in 68 cases, 87%). They were a median 18 and 38 years of age when their first neoplasm and BC were diagnosed, respectively. Breast-conserving surgery was performed in 39 patients, and 32 underwent breast irradiation. Twenty of the 41 patients (49%) treated with chemotherapy received an anthracycline-containing regimen.The 5- and 11-year event free survival (EFS) and overall survival (OS) rates were 69% and 42%, respectively. Nine patients (12%) developed a third cancer and 18 (23%) a cardiovascular event. Of the 68 women with invasive BC, the first event involved contralateral BC in 55% of cases: time to progression (TTP) rates were 70% and 47% at 5 and 11 years. The 5- and 11-year BC-specific survival rates (BCSS) were 84% and 68%, respectively.ConclusionsJudging from our experience, survival rates after BC developing in women previously given chest radiotherapy are not dissimilar to those observed in other women with primary BC. Given the far from negligible risk of subsequent cancers and cardiovascular events, it is mandatory to discuss the best choice of treatment for such patients in terms of their chances of cure and quality of life, and also the risks of late sequelae.     

Individualized estimates of second cancer risks after contemporary radiation therapy for Hodgkin lymphoma

BACKGROUND: Estimates of radiation-related second cancer risk among Hodgkin lymphoma survivors are largely based on radiation therapy (RT) fields and doses no longer in use, and these estimates do not account for differences in normal tissue dose among individual patients. This study gives individualized estimates for the risks of lung and female breast cancer expected with contemporary involved-field RT and low-dose (20 Gy) RT for mediastinal Hodgkin lymphoma. METHODS: Three RT plans were constructed for 37 consecutive patients with mediastinal Hodgkin lymphoma: 35 Gy mantle RT, 35 Gy involved-field RT (IFRT), and 20 Gy IFRT. For each of the 111 RT plans, individual-level dosimetry data were incorporated into a cell initiation/inactivation/proliferation model to estimate the excess relative risk (ERR) and cumulative incidence of radiation-induced second cancer. RESULTS: ERR estimates were compatible with results of epidemiological studies. Compared with 35 Gy mantle radiation therapy, 35 Gy IFRT was predicted to reduce the 20-year ERRs of breast and lung cancer by 63% and 21%, respectively, primarily because of lower normal tissue doses with the omission of axillary RT. Low-dose (20 Gy) IFRT was associated with a 77% and 57% decrease in these ERRs. Patient-specific differences in normal tissue dose with IFRT led to 11-fold and 3.6-fold variations among individual's estimates of breast and lung cancer ERR, respectively. CONCLUSIONS: Contemporary IFRT is predicted to substantially reduce risk of secondary breast and lung cancer compared with mantle RT, with considerable variation in risk among individuals. Individualized prospective risk estimates could facilitate patient-specific counseling and the development of more effective RT techniques.     

Parenthood after cancer - a population-based study

Many cancer forms today have good prognosis, and parenthood after cancer diagnosis and treatment has become a central research topic. Previous research has mainly focused on reproductive cancers, and few population-based studies exist.The effect of several cancer forms on fertility at a population level was explored. Discrete-time hazard regression models were used to analyse register and census data for complete Norwegian birth cohorts. Men and women 17-44 years in the period 1965-2001 were included. Models for first- and higher-order birth rates, for men and women, were estimated.Overall, first-birth rates among persons with cancer were reduced by only about 25% when compared with the general population. Male cancer survivors' second- and third-birth rates were similarly reduced, whereas higher-order birth rates for females were 36% below those of the general population. Significant decreases in cancer survivors' fertility disadvantage relative to the general population were seen from 1965 to 2001.Reductions in fertility were most pronounced for reproductive cancer forms, presumably related to subfecundity. However, also cancer forms unrelated to reproductive function led to reduced fertility, perhaps suggesting underlying social mechanisms. This is further supported by the difference in probability between first and subsequent births observed for women.     

Fecal microbiota diversity in survivors of adolescent/young adult Hodgkin lymphoma: a study of twins

Background:

Adolescent/young adult Hodgkin lymphoma (AYAHL) survivors report fewer exposures to infections during childhood compared with controls, and they have functional lymphocyte aberrations. The gut microbiota plays a central role in immunity.

Methods:

We investigated whether fecal microbial diversity differed between 13 AYAHL survivors and their unaffected co-twin controls. Pyrosequencing of fecal bacterial 16S rRNA amplicons yielded 252 943 edited reads that were assigned to species-level operational taxonomic units (OTUs) and standardised for sequencing depth by random sampling. Microbial diversity was compared within vs between twin pairs and by case–control status.

Results:

The number of unique OTUs was more similar within twin pairs compared with randomly paired participants (P=0.0004). The AYAHL cases had fewer unique OTUs compared with their co-twin controls (338 vs 369, P=0.015); this difference was not significant (169 vs 183, P=0.10) when restricted to abundant OTUs.

Conclusion:

In this small study, AYAHL survivors appear to have a deficit of rare gut microbes. Further work is needed to determine if reduced microbial diversity is a consequence of the disease, its treatment, or a particularly hygienic environment.     

Health‐related quality of life among survivors of aggressive non‐Hodgkin lymphoma

BACKGROUND:

Non‐Hodgkin lymphoma (NHL) is the fifth most common cancer among men and women. Patients with aggressive NHL receive intense medical treatments that can significantly compromise health‐related quality of life (HRQOL). However, knowledge of HRQOL and its correlates among survivors of aggressive NHL is limited.

METHODS:

Self‐reported data on HRQOL (physical and mental function, anxiety, depression, and fatigue) were analyzed for 319 survivors of aggressive NHL. Survivors 2 to 5 years postdiagnosis were selected from the Los Angeles County Cancer Registry. Bivariate and multivariable methods were used to assess the influence of sociodemographic, clinical, and cognitive health‐appraisal factors on survivors' HRQOL.

RESULTS:

After accounting for other covariates, marital status was associated with all HRQOL outcomes (P < .05). Younger survivors reported worse mental function and higher levels of depression, anxiety, and fatigue (P < .01). Survivors who had more comorbid conditions or lacked private health insurance reported worse physical and mental function and higher levels of depression and fatigue (P < .05). Survivors who experienced a recurrence reported worse physical function and higher levels of depression and fatigue (P < .05). With the exception of a nonsignificant association between perceived control and physical function, greater perceptions of personal control and health competence were associated significantly with more positive HRQOL outcomes (P < .01).

CONCLUSIONS:

The current results indicated that survivors of aggressive NHL who are younger, are unmarried, lack private insurance, or experience greater illness burden may be at risk for poorer HRQOL. Cognitive health‐appraisal factors were strongly related to HRQOL, suggesting potential benefits of interventions focused on these mutable factors for this population. Cancer 2013. © 2012 American Cancer Society.     

Birth weight and risk of paediatric Hodgkin lymphoma: Findings from a population-based record linkage study in California

ObjectiveTo evaluate the relationship between birth weight (along with a variety of pre and perinatal characteristics) and the risk of paediatric Hodgkin lymphoma (HL) diagnosed at age <20 years.MethodWe linked California statewide birth records from 1978–2009 and cancer diagnosis data from 1988–2011 to conduct a population-based case–control study with 1216 cases and 4485 controls (matched on birth month and year, sex, and race/ethnicity). Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) of paediatric HL overall and by age of diagnosis, controlling for other perinatal factors.ResultsCompared to children with a normal birth weight (2500–3999 g), those who had a high birth weight (≥4000 g) had an increased risk of paediatric HL overall (OR = 1.23, 95% CI: 1.02–1.48) after adjusting for birth order, maternal age at the time of delivery, and paternal age at the time of delivery. The magnitude of association appeared larger for subgroups of children whose age of diagnosis was 0–10 years (OR = 1.56, 95% CI: 1.04–2.24) or 15–19 years (OR = 1.43, 95% CI: 1.11–1.83), while no association was observed in 11–14 year olds. Compared with firstborn children, those who were third or higher in birth order had a reduced risk of paediatric HL overall (OR = 0.80, 95% CI: 0.67–0.95), and this association also varied by age of diagnosis.ConclusionsIn this study with the largest number of paediatric HL cases, high birth weight was associated with an increased disease risk for most but not all ages of diagnosis. The different findings by age of diagnosis regarding both birth weight and birth order underscore the importance to stratify paediatric HL by age at diagnosis in future etiological investigations.     

Pregnancy after adolescent and adult cancer: a population-based matched cohort study

Despite fertility-preserving initiatives, postcancer reproduction is expected to be lower than that of the general population. Using data from the Cancer Registry and the Medical Birth Registry of Norway, postcancer pregnancy rates were analyzed in 27,556 survivors and compared to those from a matched comparison group ("controls") from the general population. All were born after 1950, diagnosed from 1967 to 2004 at age of 16-45, and had an observation time from the date of diagnosis (assigned date for controls), until pregnancy, death, age 46, or December 31, 2006. Cox regression was used to estimate pregnancy rates, after adjusting for educational level, parity and diagnostic period. Overall, cancer survivors had a lower pregnancy rate than the controls, but the rate for survivors was higher in males than in females [hazard rate (HR)=0.74 (95% confidence interval (CI) 0.71-0.78) and HR=0.61 (95% CI 0.58-0.64), respectively]. However, the rates did not differ between controls and survivors of malignant melanoma or thyroid cancer. By contrast, the lowest HRs for pregnancy occurred in survivors of leukemia, cervical or breast cancer. Increased pregnancy rates during the study period were detected for ovarian cancer [HR=0.2 (95% CI 0.1-0.3) to HR=0.7 (95% CI 0.5-0.9)], testicular cancer [HR=0.6 (95% CI 0.4-0.9) to HR=0.8 (95% CI 0.7-0.8)], and Hodgkin lymphoma diagnosed in men [HR=0.7 (95% CI 0.5-0.9) to HR=0.9 (95% CI 0.7-1.0)]. In summary, fertility-preserving attempts have succeeded in patients with ovarian or testicular cancer and in males with Hodgkin lymphoma. Male survivors initiated pregnancies in a higher degree than female survivors.     

Definitive radiotherapy for stage I nonsmall cell lung cancer

BACKGROUND:

The current study characterizes the overall survival (OS) and cause‐specific survival (CSS) of patients with stage I nonsmall cell lung cancer (NSCLC) who were treated with radiotherapy alone, and analyzes the variables potentially affecting survival outcomes.

METHODS:

A total of 8524 patients with stage I NSCLC (according to the sixth edition of the American Joint Committee on Cancer staging manual) who were diagnosed between 1988 and 2008 were retrospectively analyzed using the population‐based Surveillance, Epidemiology, and End Results database. Cox regression analysis was used to calculate hazard ratios (HR) from multivariate analyses.

RESULTS:

The 1‐year, 2‐year, and 5‐year OS rates were 62%, 37%, and 11%, respectively; the corresponding lung cancer CSS survival rates were 68%, 45%, and 20%, respectively. Approximately 77% of deaths were from lung cancer (5292 of 6891 total deaths). Cardiac (n = 477 deaths) and pulmonary (other than lung cancer deaths; n = 475 deaths) deaths accounted for 14% of deaths. From Cox proportional hazards analyses, male sex (HR, 1.2) and squamous cell carcinoma histology (HR, > 1.1) were found to be significantly (P < .0001) adverse prognostic factors for both OS and lung cancer CSS. A more recent calendar year of diagnosis was associated with significantly (P < .0001) improved OS (HR, 0.84 per decade) and lung cancer CSS. This trend was also significant (P < 0.0001) when restricting analyses to those patients with tumors measuring ≤ 5 cm (n = 5402 patients). T1 classification (vs T2 or T unknown) and smaller tumor size were found to be significantly (P < .0001) favorable factors.

CONCLUSIONS:

From a population‐based registry analysis of patients with stage I NSCLC, significant (albeit modest) improvements in survival in more recent years were appreciated, which likely reflect technologic advances in the diagnosis of, staging of, and radiotherapy for NSCLC. Cancer 2012. © 2012 American Cancer Society.     

U-2940, a human B-cell line derived from a diffuse large cell lymphoma sequential to Hodgkin lymphoma

Several patterns of association between Hodgkin and non-Hodgkin lymphomas are recognized, some of which support a common cellular origin or shared transformation events for both malignancies. We describe the U-2940 cell line derived from a diffuse large B-cell lymphoma with some features consistent with mediastinal large B-cell lymphoma, clinically apparent 1 month after the initial course of chemotherapy for Hodgkin's disease, fulfilling the criteria for composite malignancies. U-2940 cells display a mature B phenotype with hypermutated IgH rearrangement typical of germinal/postgerminal center origin. The cell line is negative for Epstein-Barr virus and no evidence of t(14;18) was found. U-2940 cells display multiple chromosomal rearrangements similar to recurrent aberrations described in both Hodgkin and non-Hodgkin lymphomas, also partially shared by U-2932 derived from a B-cell lymphoma sequential to Hodgkin's disease. The original large B-cell lymphoma and the U-2940 cell line bear microsatellite instability, an abnormality associated with particular subtypes of non-Hodgkin lymphomas and found in tissues involved by Hodgkin lymphoma. Therefore, U-2940 cells bear several features known to occur in Hodgkin and in non-Hodgkin lymphomas, leading to the assumption that this cell line may constitute a useful tool to address elective pathways of lymphomagenesis and eventually the Hodgkin and non-Hodgkin lymphoma association.     

Outcome of a risk-related therapeutic strategy used prospectively in a population-based study of Hodgkin's lymphoma in adolescents

The aim was to assess outcome in a population-based cohort of adolescents with Hodgkin's lymphoma (HL) diagnosed in the UK's northern region over a 10-year period. Among a population of 3.09 million, 55 of 676 patients (8%) diagnosed with HL were aged 13-19. Seven had nodular lymphocyte-predominant HL, 48 classical HL (cHL). Of the latter, 36 were >or=16 years. Application of the Scottish and Newcastle Lymphoma Group (SNLG) prognostic index meant 21 patients were considered high risk (index >or=0.5). They received PVACEBOP multi-agent chemotherapy as primary therapy. Standard risk patients (SNLG index <0.5) were treated with standard ChlVPP or ABVD chemotherapy+/-radiotherapy. Scottish and Newcastle Lymphoma Group indexing is not valid for patients under 16. Twelve patients therefore received UKCCSG protocols (n=8), ABVD plus radiotherapy (n=2), or PVACEBOP (n=2). Forty-six patients with cHL (96%) achieved complete remission. Seven patients relapsed but all entered complete remission after salvage therapy. Five patients died: three of HL, one in an accident and one of disseminated varicella complicating cystic fibrosis. Five- and 10-year overall survival was 93 and 86%, respectively; disease-specific survival was 95 and 92%. The data suggest that older adolescents with high-risk HL require intensive protocols as primary therapy to secure optimal outcome.     

Family history of cancer and risk of pediatric and adolescent Hodgkin lymphoma: A Children's Oncology Group study

Family history of lymphoid neoplasm (LN) is a strong and consistently observed Hodgkin lymphoma (HL) risk factor, although it has been only marginally examined in pediatric/adolescent patients. Here, healthy control children identified by random digit dialing were matched on sex, race/ethnicity and age to HL cases diagnosed at 0–14 years at Children's Oncology Group institutions in 1989–2003. Detailed histories were captured by structured telephone interviews with parents of 517 cases and 783 controls. Epstein–Barr virus (EBV) RNA detection was performed for 355 available case tumors. Two analytic strategies were applied to estimate associations between family cancer history and pediatric/adolescent HL. In a standard case–control approach, multivariate conditional logistic regression was used to calculate odds ratios and 95% confidence intervals (CIs). In a reconstructed cohort approach, each relative was included as a separate observation, and multivariate proportional hazards regression was used to produce hazard ratios (HRs) and 95% CIs. Using the latter, pediatric/adolescent HL was associated with a positive family history (HR = 1.20, 95% CI: 1.06–1.36), particularly early‐onset cancers (HR = 1.30, 95% CI: 1.06–1.59) and those in the paternal lineage (HR = 1.38, 95% CI: 1.16–1.65), with a suggested association for LN in first‐degree relatives (HR = 3.61, 95% CI: 0.87–15.01). There were no discernable patterns for EBV+ versus EBV– HL. The clustering of LN within pedigrees may signal shared genetic susceptibility or common environmental exposures. Heritable genetic risk variants have only recently begun to be discovered, however. These results are consistent with other studies and provide a compelling rationale for family‐based studies to garner information about genetic susceptibility to HL.     

Sequential chemotherapy in nonsmall-cell lung cancer: cisplatin and gemcitabine followed by docetaxel

BACKGROUND: Improving results in nonsmall-cell lung cancer (NSCLC) will require the development of new drugs and strategies to combine available agents. On the basis of data indicating the activity of docetaxel as second-line therapy, a Phase II study was conducted to evaluate the efficacy and toxicity of the sequential combination of chemotherapy consisting of cisplatin (P) and gemcitabine (G) followed by docetaxel (DOC) in patients with advanced NSCLC. METHODS: Patients with 1997 TNM stage IIIB (pleural effusion)/stage IV NSCLC, performance status (PS) of 0-1, and normal organ function were eligible. Therapy consisted of P at 75 mg/m(2) on Day 1 and G 1200 mg/m(2) on Days 1 and 8 every 3 weeks for 3 cycles followed, in nonprogressive patients, by DOC 30 mg/m(2) every week for 6 consecutive weeks every 8 weeks for 2 cycles. RESULTS: Fifty-two eligible patients were enrolled (M/F, 39/13; stage IIIB/IV, 8/44; PS 0, 73%, PS 1, 27%; median age, 58 years; range, 36-73). The overall response rate was 36.5% (95% confidence interval [CI]: 23-49). The median overall survival was 11 months (95% CI: 9-13); the median progression-free survival was 6 months (95% CI: 5-7); and the 1- and 2-year survivals were 48% and 25%, respectively. One- and 2-year progression-free survivals were 12% and 8%, respectively. Both phases of the treatment protocol were well tolerated. CONCLUSIONS: P/G followed by weekly DOC is well tolerated and active as first-line therapy for NSCLC patients and provides a feasible chemotherapeutic option in this clinical setting.     

The impact of EBV and HIV infection on the microenvironmental niche underlying Hodgkin lymphoma pathogenesis

The pathogenesis of classical Hodgkin lymphoma (cHL) is still enigmatic, largely because its tumor cells, the so‐called Hodgkin and Reed–Stenberg (HRS) cells, invariably reside in a prominent reactive microenvironment, are rare and therefore difficult to analyze. On the other hand, the broadly investigated cHL‐derived cell lines are not unequivocally considered as suitable and representative models for this puzzling disease. Based on current knowledge, it appears that the cross talk between the tumor cells and the reactive infiltrate of the microenvironment is complex and that multiple mechanisms occur, making cHL a very heterogeneous disease. In 20–40% of cHL cases, HRS cells carry a monoclonal infection by Epstein Barr virus (EBV), which is considered a tumor‐initiating factor. In these cases, EBV shows a latency type II infection pattern with the expression of latent membrane protein‐1 (LMP‐1), a viral oncoprotein that mimics CD40 activation. This scenario is particularly intriguing for the pathogenesis of cHL arising in HIV‐infected patients, which, for still obscure reasons, is invariably EBV‐associated with LMP‐1 expression in HRS cells. Recent evidences are consistent with the occurrence of different pathogenic pathways variably triggered by virus infections (EBV and HIV), genetic alterations, and interactions with critical microenvironmental components. This review focuses on the different microenvironmental niches that characterize cHL of the general population as well as cases of HIV‐infected patients. A more comprehensive understanding of the complex interplay existing between HRS and tumor microenvironment is pivotal for the development of more effective treatments, particularly for relapsed or refractory diseases.