Leukaemia and myeloid malignancy among people exposed to low doses (<100 mSv) of ionising radiation during childhood: a pooled analysis of nine historical cohort studies.

BACKGROUND: Substantial evidence links exposure to moderate or high doses of ionising radiation, particularly in childhood, with increased risk of leukaemia. The association of leukaemia with exposure to low-dose (<100 mSv) radiation is less certain, although this is the dose range most relevant to the general population. We aimed to estimate the risk of leukaemia associated with low-dose radiation exposure in childhood (age <21 years). METHODS: In this analysis of historical cohort studies, we pooled eligible cohorts reported up to June 30, 2014. We evaluated leukaemia and myeloid malignancy outcomes in these cohorts with the relevant International Classification of Diseases and International Classification of Diseases for Oncology definitions. The cohorts included had not been treated for malignant disease, had reported at least five cases of the relevant haematopoietic neoplasms, and estimated individual active bone marrow (ABM) doses. We restricted analysis to individuals who were younger than 21 years at first irradiation who had mean cumulative ABM doses of less than 100 mSv. Dose-response models were fitted by use of Poisson regression. The data were received in fully anonymised form by the statistical analyst. FINDINGS: We identified nine eligible cohorts from Canada, France, Japan, Sweden, the UK, and the USA, including 262 573 people who had been exposed to less than 100 mSv enrolled between June 4, 1915, and Dec 31, 2004. Mean follow-up was 19·63 years (SD 17·75) and mean cumulative ABM dose was 19·6 mSv (SD 22·7). 154 myeloid malignancies were identified (which included 79 acute myeloid leukaemias, eight myelodysplastic syndromes, and 36 chronic myeloid leukaemias, in addition to other unspecified myeloid malignancies) and 40 acute lymphoblastic leukaemias, with 221 leukaemias (including otherwise unclassified leukaemias but excluding chronic lymphocytic leukaemia) identified overall. The fitted relative risks at 100 mSv were 3·09 (95% CI 1·41-5·92; ptrend=0·008) for acute myeloid leukaemia and myelodysplastic syndromes combined, 2·56 (1·09-5·06; ptrend=0·033) for acute myeloid leukaemia, and 5·66 (1·35-19·71; ptrend=0·023) for acute lymphoblastic leukaemia. There was no clear dose-response for chronic myeloid leukaemia, which had a relative risk at 100 mSv of 0·36 (0·00-2·36; ptrend=0·394). There were few indications of between-cohort heterogeneity or departure from linearity. For acute myeloid leukaemia and myelodysplastic syndromes combined and for acute lymphoblastic leukaemia, the dose-responses remained significant for doses of less than 50 mSv. Excess absolute risks at 100 mSv were in the range of 0·1-0·4 cases or deaths per 10 000 person-years. INTERPRETATION: The risks of acute myeloid leukaemia and acute lymphoblastic leukaemia were significantly increased after cumulative doses of ionising radiation of less than 100 mSv in childhood or adolescence, with an excess risk also apparent for cumulative radiation doses of less than 50 mSv for some endpoints. These findings support an increased risk of leukaemia associated with low-dose exposure to radiation and imply that the current system of radiological protection is prudent and not overly protective. FUNDING: National Cancer Institute Intramural Research Program, National Cancer Institute, and US National Institutes for Health.

Case report: An HIV+ patient presenting with pancytopenia, hepatic failure, and coagulopathy; a rare small cell liver carcinoma with diffuse splenic and bone marrow metastasis diagnosed at autopsy.

A 34-year old male with a giant condyloma acuminatum of the anus secondary to HIV infection presented to the emergency department with a persistent nose bleed lasting 2-3days, acute anemia, thrombocytopenia, and coagulopathy. The patient also had significant hepatosplenomegaly and elevated liver enzymes which were a new finding since the patient's last hospitalization 1-2month prior to the current admission. A bone marrow biopsy showed diffuse infiltration by carcinoma with neuroendocrine features. The patient quickly developed multi-organ injury, decompensated, and died. An autopsy was obtained which established the diagnosis of small cell carcinoma of the liver.

A case of disseminated carcinomatosis of the bone marrow originating from gastric cancer 3 years after intraperitoneal chemotherapy against peritoneal carcinomatosis.

BACKGROUND: Clinical studies of intraperitoneal chemotherapy with paclitaxel in patients of gastric cancer with peritoneal carcinomatosis is well tolerated and effective, and rare cases of metastasis and recurrence have experienced during the treatment. Disseminated carcinomatosis of the bone marrow is highly rare in gastric cancer and associated with a poor prognosis. CASE PRESENTATION: A 59-year-old woman of gastric cancer with peritoneal carcinomatosis received five courses of chemotherapy with intraperitoneal administration of paclitaxel, and laparoscopy showed disappearance of the peritoneal carcinomatosis. She subsequently underwent total gastrectomy, and the histopathological findings showed a complete response to the chemotherapy. Postoperatively, chemotherapy with intraperitoneal administration of paclitaxel was continued for 30 months, without apparent recurrence. However, the gastric cancer recurred as disseminated carcinomatosis of the bone marrow with disseminated intravascular coagulation, and we hence changed the chemotherapy regimen to weekly irinotecan. Remission was achieved, and she did not experience any major symptoms; however, she died 6 months after the diagnosis of disseminated carcinomatosis of the bone marrow. CONCLUSIONS: Since intraperitoneal paclitaxel administration can strongly suppress peritoneal carcinomatosis of gastric cancer, careful attention should be paid not only to peritoneal recurrence but also for rare site metastases, such as bone marrow metastases.

Secondary bone marrow malignancies after adjuvant chemotherapy for breast cancer: a report of 2 cases and a review of the literature.

PURPOSE: Secondary malignancies are new cancers occurring in patients previously treated with radiation or chemotherapy for a primary tumor. Secondary cancers are not related to the primary tumor, and may develop months or years after cancer treatment: they are usually a result of the first cancer therapy. Chemotherapy and radiotherapy may increase the risk of second cancers, such as skin tumors (basal or squamous cell carcinoma) or acute leukemia. METHODS: A patient with B-lymphoma and a patient with multiple myeloma, previously treated for breast cancer, are presented. RESULTS: We report the cases of 2 patients treated with adjuvant therapy for breast cancer who developed secondary bone marrow malignancies 15 years after primary treatment. CONCLUSIONS: By literature review, these 2 cases do not support the relationship between primary tumor treatment and secondary cancer, but strongly suggest the need for histologic samples when bone metastasis occurred after years from diagnosis of breast cancer. In this setting, the oncologist should take into account a secondary bone marrow tumor before starting treatment for breast cancer.

Bone marrow biopsy in patients with renal transplant: spectrum of findings and diagnostic use.

OBJECTIVES: Renal transplant may be complicated by cytopenia, fever of unknown etiology, or hematolymphoid malignancies. Bone marrow biopsy may be indicated to evaluate these complications. However, to the best of our knowledge, no previous study has systematically documented the characteristics of bone marrow biopsy in these patients. The present study reports the range of bone marrow findings in renal transplant recipients. MATERIALS AND METHODS: We selected 85 patients who underwent bone marrow biopsy among 1745 renal transplant recipients who had transplant at Ba skent University from January 1990 to December 2013. The files of these patients were reviewed for age, sex, age at renal transplant, underlying renal disease, donor type, immunosuppressive therapy, presence or absence of acute humoral or cellular rejection, duration between transplant and bone marrow biopsy, indication for bone marrow biopsy, and histopathologic diagnoses of bone marrow biopsies. RESULTS: The most common cause of renal insufficiency leading to transplant in this patient group was unknown etiology, observed in 24 patients (28.2%). The most common indication for bone marrow biopsy was blood cytopenia, detected in 56 patients (65.9%). Neoplastic involvement of the bone marrow was detected in 6 patients (7.1%), all of which were hematolymphoid malignancies. Corticosteroids were the most commonly used immunosuppressive agents, administered to all patients. CONCLUSIONS: Bone marrow biopsy provides important information in renal transplant recipients, especially in cases of neoplastic bone marrow involvement, specific inflammation, and amyloidosis, which are uncommon in this patient group. The overall diagnostic use is related to the individual situation of each patient.

Risk of marrow neoplasms after adjuvant breast cancer therapy: the national comprehensive cancer network experience.

PURPOSE: Outcomes for early-stage breast cancer have improved. First-generation adjuvant chemotherapy trials reported a 0.27% 8-year cumulative incidence of myelodysplastic syndrome/acute myelogenous leukemia. Incomplete ascertainment and follow-up may have underestimated subsequent risk of treatment-associated marrow neoplasm (MN). PATIENTS AND METHODS: We examined the MN frequency in 20,063 patients with stage I to III breast cancer treated at US academic centers between 1998 and 2007. Time-to-event analyses were censored at first date of new cancer event, last contact date, or death and considered competing risks. Cumulative incidence, hazard ratios (HRs), and comparisons with Surveillance, Epidemiology, and End Results estimates were obtained. Marrow cytogenetics data were reviewed. RESULTS: Fifty patients developed MN (myeloid, n = 42; lymphoid, n = 8) after breast cancer (median follow-up, 5.1 years). Patients who developed MN had similar breast cancer stage distribution, race, and chemotherapy exposure but were older compared with patients who did not develop MN (median age, 59.1 v 53.9 years, respectively; P = .03). Two thirds of patients had complex MN cytogenetics. Risk of MN was significantly increased after surgery plus chemotherapy (HR, 6.8; 95% CI, 1.3 to 36.1) or after all modalities (surgery, chemotherapy, and radiation; HR, 7.6; 95% CI, 1.6 to 35.8), compared with no treatment with chemotherapy. MN rates per 1,000 person-years were 0.16 (surgery), 0.43 (plus radiation), 0.46 (plus chemotherapy), and 0.54 (all three modalities). Cumulative incidence of MN doubled between years 5 and 10 (0.24% to 0.48%); 9% of patients were alive at 10 years. CONCLUSION: In this large early-stage breast cancer cohort, MN risk after radiation and/or adjuvant chemotherapy was low but higher than previously described. Risk continued to increase beyond 5 years. Individual risk of MN must be balanced against the absolute survival benefit of adjuvant chemotherapy.

Peripheral blood abnormalities and bone marrow infiltration in canine large B-cell lymphoma: is there a link?

Official guidelines do not consider bone marrow (BM) assessment mandatory in staging canine lymphoma unless blood cytopenias are present. The aim of this study was to find out if blood abnormalities can predict marrow involvement in canine large B-cell lymphoma. BM infiltration was assessed via flow cytometry. No difference was found between dogs without haematological abnormalities and dogs with at least one. However, the degree of infiltration was significantly higher in dogs with thrombocytopenia, leucocytosis or lymphocytosis and was negatively correlated to platelet count and positively to blood infiltration. Our results suggest that blood abnormalities are not always predictive of marrow involvement, even if thrombocytopenia, leucocytosis or lymphocytosis could suggest a higher infiltration. BM evaluation should therefore be included in routine staging in order not to miss infiltrated samples and to improve classification. However, its clinical relevance and prognostic value are still not defined and further studies are needed.

[Research on molecular markers for epigenetic changes in myeloid malignancies].

Novel recurrent somatic mutations have been identified in patients with myeloid malignancies including myeloproliferative neoplasms (MPNs), myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). Mutations of tet methylcytosine dioxygenase 2 (TET2), DNA methyltransferase 3A (DNMT3A), isocitrate dehydrogenase (IDH)1/2, enhancer of zeste homologue 2 (EZH2) and additional sex combs-like 1 (ASXL1) have been shown to play important roles in the regulation of epigenetic patterning, and may be used as molecular predictors for pathogenesis and clinical outcome for patients with myeloid malignancies.

Chronic inflammation as a promotor of mutagenesis in essential thrombocythemia, polycythemia vera and myelofibrosis. A human inflammation model for cancer development?

The Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) are acquired stem cell neoplasms, in which a stem cell lesion induces an autonomous proliferative advantage. In addition to the JAK2V617 mutation several other mutations have been described. Recently chronic inflammation has been proposed as a trigger and driver of clonal evolution in MPNs. Herein, it is hypothesized that sustained inflammation may elicit the stem cell insult by inducing a state of chronic oxidative stress with elevated levels of reactive oxygen species (ROS) in the bone marrow, thereby creating a high-risk microenvironment for induction of mutations due to the persistent inflammation-induced oxidative damage to DNA in hematopoietic cells. Alterations in the epigenome induced by the chronic inflammatory drive may likely elicit a "epigenetic switch" promoting persistent inflammation. The perspectives of chronic inflammation as the driver of mutagenesis in MPNs are discussed, including early intervention with interferon-alpha2 and potent anti-inflammatory agents (e.g. JAK1-2 inhibitors, histone deacetylase inhibitors, DNA-hypomethylators and statins) to disrupt the self-perpetuating chronic inflammation state and accordingly eliminating a potential trigger of clonal evolution and disease progression with myelofibrotic and leukemic transformation.

Perspectives on chronic inflammation in essential thrombocythemia, polycythemia vera, and myelofibrosis: is chronic inflammation a trigger and driver of clonal evolution and development of accelerated atherosclerosis and second cancer?

The morbidity and mortality of patients with the chronic Philadelphia-negative myeloproliferative neoplasms (MPNs), essential thrombocythemia, polycythemia vera, and primary myelofibrosis are mainly caused by cardiovascular diseases, thrombohemorrhagic complications, and bone marrow failure because of myelofibrosis and leukemic transformation. In the general population, chronic inflammation is considered of major importance for the development of atherosclerosis and cancer. MPNs are characterized by a state of chronic inflammation, which is proposed to be the common denominator for the development of "premature atherosclerosis," clonal evolution, and second cancer in patients with MPNs. Chronic inflammation may both initiate clonal evolution and catalyze its expansion from early disease stage to the myelofibrotic burnt-out phase. Furthermore, chronic inflammation may also add to the severity of cardiovascular disease burden by accelerating the development of atherosclerosis, which is well described and recognized in other chronic inflammatory diseases. A link between chronic inflammation, atherosclerosis, and second cancer in MPNs favors early intervention at the time of diagnosis (statins and interferon-α2), the aims being to dampen chronic inflammation and clonal evolution and thereby also diminish concurrent disease-mediated chronic inflammation and its consequences (accelerated atherosclerosis and second cancer).

Minimal residual disease is a prognostic marker for neuroblastoma with bone marrow infiltration.

OBJECTIVE: This pilot study focused on whether flow cytometry (FCM) detection of minimal residual disease in bone marrow (BM) could predict the outcome of patients with advanced neuroblastoma (NB). PATIENTS AND METHODS: Fifty-seven stage 4 NB patients with BM infiltration were enrolled in this study. All of them received NB-2001 protocol. BM samples were examined for tumor cell contamination by both morphology and FCM with CD45-FITC/CD81-PE/CD56-PECy5 monoclonal antibodies cocktail at diagnosis and after 4 courses of chemotherapy. RESULTS: BM samples of all patients were positive at diagnosis by FCM, and samples from 30 patients became negative after 4 courses of chemotherapy, 10 patients relapsed (33.3%) in mean 45.5 months, range 7 to 69. Another 27 patients remained positive, and 20 of them relapsed (74.1%) in mean 24.2 months, range 8 to 48. There was a statistically significant difference in event-free survival between the 2 groups (P = 0.002). CONCLUSIONS: Persistence of minimal residual disease in BM may work as a chemotherapy response marker and predict the prognosis in advanced NB.

Hepatic lymphomas post renal transplantation may signify worse disease behavior: analysis of data from 26 international studies.

INTRODUCTION: Hepatic involvement by posttransplant lymphoproliferative disorders (PTLD) is an important but rarely investigated issue. In the current study, we aimed to pool data of cases of PTLD localization in liver (L-PTLD) among renal allograft recipients from different series to find new perspectives on the disease. METHODS: We conducted a comprehensive search for the available data through PubMed and Google Scholar for reports of PTLD localization in the liver and surrounding lymph nodes in renal allograft recipients. Data of 232 cases from 26 international studies have been pooled and reanalyzed. RESULTS: Patients with L-PTLD were significantly more likely to be of male gender (P=0.02). Death due to PTLD was higher in L-PTLD patients (P=0.06). Disseminated PTLD, based on our definition, was significantly more prevalent in L-PTLD than in none-liver-PTLD (NL-PTLD) (P < 0.001); the same finding was noted with multi-organ involvement which was significantly higher in L-PTLD (P<0.001). L-PTLD was significantly more likely to complicate heart (P=0.03), bone marrow (P=0.002), spleen (P=0.01), and kidney allograft Involvement (P=0.04). CONCLUSION: We conclude that renal transplant patients exhibiting liver localization for PTLD should be carefully followed for multi-organ involvement. Most notably, bone marrow biopsy should be considered, and evaluations for renal allograft, heart and spleen localization for PTLD should be executed. Due to the unfavorable characters of liver localization by PTLD in renal recipients, we propose higher levels of evaluations and follow up for these patients. Prospective studies with larger patient populations are needed to confirm our results.

Persistence of disseminated tumor cells in the bone marrow of breast cancer patients predicts increased risk for relapse--a European pooled analysis.

BACKGROUND: The prognostic significance of disseminated tumor cells (DTC) in bone marrow (BM) of breast cancer patients at the time of primary diagnosis has been confirmed by a large pooled analysis. In view of the lack of early indicators for secondary adjuvant treatment, we here evaluated whether the persistence of DTCs after adjuvant therapy increases the risk of subsequent relapse and death. PATIENTS AND METHODS: Individual patient data from 676 women with primary diagnosis of early breast cancer stages I-III from 3 follow-up studies were pooled. During clinical follow-up, patients underwent BM aspiration (BMA) to determine the presence of DTC. Tumor cells were detected by the standardized immunoassays. Univariate and multivariable proportional hazards models were estimated to assess the prognostic significance of DTC for disease-free survival (DFS) and overall survival (OS). RESULTS: Patients were followed for a median of 89 months. BMA was performed at median 37 months after diagnosis of breast cancer. At follow-up BMA, 15.5% of patients had DTCs. The presence of DTC was an independent indicator of poor prognosis for DFS, distant DFS (DDFS), cancer-specific survival, and OS during the first 5 years following cancer diagnosis (log-rank test P < 0.001 values for all investigated endpoints). CONCLUSION: Among breast cancer patients, persistent DTCs during follow-up significantly predicted the increased risk for subsequent relapse and death. Analysis of DTC might serve as a clinically useful monitoring tool and should be tested as an indicator for secondary adjuvant treatment intervention within clinical trials.

[A case of poorly differentiated adenocarcinoma of the rectum with disseminated carcinomatosis of the bone marrow successfully treated with mFOLFOX-6/bevacizumab].

A 45-year-old woman, complaining of back pain and bloody stool was given a diagnosis of poorly differentiated adenocarcinoma of the rectum with disseminated carcinomatosis to bone marrow and disseminated intravascular coagulation syndrome (DIC). We started chemotherapy using mFOLFOX-6 with simultaneous DIC treatment. After we confirmed that DIC had improved following 2 courses of mFOLFOX-6, bevacizumab was added to mFOLFOX-6. Laboratory studies revealed a serum CEA level of 314.4ng/ml, which improved to 4.6ng/ml after a total of 6 courses of chemotherapy. Colonoscopy findings showed almost normal rectal mucosa after a total of 10 courses of chemotherapy. Outpatient treatment was started after 5 courses of chemotherapy, and was continuing according to schedule at 7 months from the onset of this disease.

A hematopoietic stromal lesion associated with fractionated radiotherapy (FxRT): time- and dose-effects.

Earlier, we reported that the local exposure of femoral bone marrow to a clinically-relevant course of fractionated radiotherapy [FxRT; 2.0 Gy (q24h x 5) --> 74 Gy] resulted in the delayed appearance of a stromal lesion which temporally appeared after exposures to a threshold dose of 20 Gy FxRT. To further define this threshold dose, the temporal recovery of blood-forming elements ("cobblestone area" forming colonies; CAFC(7-28d)) and the microenvironmental stroma (long-term bone marrow cultures; LTBMC) of the marrow was examined over a 17-week period following 10 and 30 Gy FxRT. After a subthreshold dose of 10 Gy, each of the 4 CAFC subpopulations were significantly dampened, with recovery initiated within a 6-week interval of 10 Gy of FxRT. Above the threshold dose (30 Gy FxRT), the CAFC subpopulations were again reduced to a level similar to that observed with 10 Gy FxRT. However, after exposures to 30 Gy FxRT, CAFC recovery was significantly well beyond the 6-week interval observed with a 10 Gy Dose of FxRT. Similarly, cell production in LTBMC prepared from marrow exposed to either 10 or 30 Gy FxRT was significantly dampened for at least 3 weeks following the FxRT. Moreover, while cell production in LTBMC derived from marrow exposed to 10 Gy was eventually restored to normal, the dampened cell production observed in LTBMC prepared after 30 Gy FxRT persisted for a period in excess of 17 weeks. Collectively, these observations provide additional support to our earlier observation suggesting that FxRT generates two forms of dose-dependent damage in the marrow: the first an early lesion arising in the blood-forming CAFC subpopulations; the second form, a delayed lesion that involves the persistent expression of a dysfunctional microenvironmental phenotype, appearing to disrupt the normal regulation of hematopoietic stem cell (HSC) proliferation and differentiation of the HSC during the recovery process.

Bone marrow abnormalities in HIV disease.

Bone marrow abnormalities are frequently observed in HIV infected individuals at all stages of the disease. The most common abnormal finding is dysplasia affecting one or more cell lines. Erythroid dysplasia is the most common type of dysplasia and is recognized in over 50% of HIV infected patients, abnormal granulocytic and megakaryocytic development is encountered in one-third of patients. Plasma cells are strikingly increased in bone marrow of HIV infected patients. It may represent a physiological response to antigenic stimulation by viruses, other infective agents or secondary to dysregulated B-cell proliferation due to HIV. Herein we present a review discussing the various bone marrow abnormalities associated with the HIV disease.

Bone marrow involvement in patients with nodular lymphocyte predominant Hodgkin lymphoma.

The significance of bone marrow involvement in patients with nodular lymphocyte predominant Hodgkin lymphoma is unknown. Of 275 patients diagnosed as lymphocyte predominant Hodgkin lymphoma at our institution (1983-2003), we identified 7 patients with purely nodular disease in the diagnostic lymph node biopsy specimen who also had bone marrow involvement. The latter was detected at the time of initial diagnosis in four patients, after one cycle of chemotherapy in one patient, and at relapse in two patients. There were six men and one woman with a median age of 37 years (range, 25-47 years). In all cases, the bone marrow was involved by large B cells, representing <10% of all cells, associated with a prominent T-cell and histiocytic background. All patients had laboratory, radiologic, and/or morphologic evidence of aggressive disease at the time of detection of bone marrow involvement. At last follow-up, four patients had died of their disease and three were alive following therapy. In conclusion, a small subset of patients in whom lymph node biopsy shows nodular lymphocyte predominant Hodgkin lymphoma with a purely nodular pattern also may have lymphoma in the bone marrow. Bone marrow involvement is associated with laboratory, radiologic, or morphologic evidence of aggressive disease and poor prognosis. Although the best terminology for these bone marrow lymphomas is uncertain, the aggressive clinical behavior of these neoplasms supports the need for intensive therapy.