A retrospective examination of mean relative telomere length in the Tasmanian Familial Hematological Malignancies Study.

Telomere length has a biological link to cancer, with excessive telomere shortening leading to genetic instability and resultant malignant transformation. Telomere length is heritable and genetic variants determining telomere length have been identified. Telomere biology has been implicated in the development of hematological malignancies (HMs), therefore, closer examination of telomere length in HMs may provide further insight into genetic etiology of disease development and support for telomere length as a prognostic factor in HMs. We retrospectively examined mean relative telomere length in the Tasmanian Familial Hematological Malignancies Study using a quantitative PCR method on genomic DNA from peripheral blood samples. Fifty-five familial HM cases, 191 unaffected relatives of familial HM cases and 75 non-familial HM cases were compared with 758 population controls. Variance components modeling was employed to identify factors influencing variation in telomere length. Overall, HM cases had shorter mean relative telomere length (p=2.9×10-6) and this was observed across both familial and non-familial HM cases (p=2.2x10-4 and 2.2x10-5, respectively) as well as additional subgroupings of HM cases according to broad subtypes. Mean relative telomere length was also significantly heritable (62.6%; p=4.7x10-5) in the HM families in the present study. We present new evidence of significantly shorter mean relative telomere length in both familial and non-familial HM cases from the same population adding further support to the potential use of telomere length as a prognostic factor in HMs. Whether telomere shortening is the cause of or the result of HMs is yet to be determined, but as telomere length was found to be highly heritable in our HM families this suggests that genetics driving the variation in telomere length is related to HM disease risk.

Anticipation in familial hematologic malignancies.

We describe a collection of 11 families with ≥ 2 generations of family members whose condition has been diagnosed as a hematologic malignancy. In 9 of these families there was a significant decrease in age at diagnosis in each subsequent generation (anticipation). The mean age at diagnosis in the first generation was 67.8 years, 57.1 years in the second, and 41.8 years in the third (P < .0002). This was confirmed in both direct parent-offspring pairs with a mean reduction of 19 years in the age at diagnosis (P = .0087) and when the analysis was repeated only including cases of mature B-cell neoplasm (P = .0007). We believe that these families provide further insight into the nature of the underlying genetic mechanism of predisposition in these families.

Evidence for a common genetic aetiology in high-risk families with multiple haematological malignancy subtypes.

A family history of a haematological malignancy (HM) is known to be a risk factor for HMs. However, collections of large families with multiple cases of varied disease types are relatively rare. We describe a collection of 12 families with dense aggregations of multiple HM subtypes. Cases were ascertained from a population based study conducted between 1972 and 1980 in Tasmania, Australia. Diagnoses were confirmed through review and re-examination of stored tissue, pathology reports, Tasmanian Cancer Registry and flow cytometry records. Family trees were generated and kinship coefficients were calculated for all pairs of affected individuals. 120 cases were found in these families. Cases diagnosed with chronic lymphocytic leukaemia (CLL) demonstrated the most significantly increased aggregation (P < 0.0001). There was also significant evidence that those individuals diagnosed at an older age (>53 years), did not aggregate together in families with disease that presented at an earlier age (<20 years) (P = 0.009).

Accuracy and clinical utility of the CoaguChek XS portable international normalised ratio monitor in a pilot study of warfarin home-monitoring.

AIM: To evaluate the accuracy of the CoaguChek XS international normalised ratio (INR) monitor compared with the laboratory method. METHODS: The accuracy and ease of use of the recently marketed CoaguChek XS portable INR monitor was evaluated in 17 patients involved in a trial of warfarin home monitoring. INR results from the monitor were compared with those from the laboratory method. Clinical applicability was measured by discrepant INR values, defined in the literature by expanded and narrow agreement criteria, and by the proportion of INR values differing by >15% and by >20% from those derived by the laboratory method. RESULTS: Participants provided 59 comparison INR measurements for analysis. The paired results were highly correlated (r = 0.91). Expanded and narrow agreement between paired INR values occurred 100% of the time. Only three CoaguChek XS (5.1%) results differed by >15% compared with the laboratory method; no results differed by >20% or were discrepant by >0.5 INR units. CONCLUSIONS: In the hands of patients the CoaguChek XS showed good correlation with laboratory determination of INR and compared well with expanded and narrow clinical agreement criteria. Both patients and doctors were highly satisfied with the accuracy and ease of use of the CoaguChek XS.

Accuracy and clinical usefulness of the near-patient testing CoaguChek S international normalised ratio monitor in rural medical practice.

OBJECTIVE: To compare the accuracy and clinical usefulness of the near-patient testing CoaguChek S INR monitor in rural medical practice. DESIGN, SETTING AND MAIN OUTCOME MEASURES: General practices were identified through Australian university departments of rural health. Study investigators trained general practitioners and/or practice nurses in the use of the CoaguChek S INR monitor. General practices obtained a fingerprick sample for testing with the INR monitor to compare with conventional pathology testing for accuracy. An evaluation questionnaire was administered to users of the machine to assess ease of use and clinical usefulness. RESULTS: A total of 169 patients from 15 general practice sites provided 401 paired (CoaguChek S and laboratory) INR results. The CoaguChek S was found to be accurate when compared to laboratory INR (r = 0.89), despite complicating variables such as multiple users of the monitor and multiple laboratories used for comparison with the CoaguChek S INR. Overall, 88% of dual INR measurements were within 0.5 INR units of each other. For laboratory INR /= 3.6, 97%, 90% and 57% of readings were within 0.5 INR units, respectively. Clinical agreement occurred 93% and 90% of the time against published expanded and narrow criteria, respectively. CONCLUSIONS: The routine use of near-patient testing, with appropriate training and quality assurance programs, has the potential to increase the safety and efficacy of warfarin therapy in rural and remote communities.

Cryopreserved human haematopoietic stem cells retain engraftment potential after extended (5-14 years) cryostorage.

Harvesting of stem cells during the early phases of treatment with no immediate intention to perform a stem cell transplant is becoming an increasingly common practice. Such "insurance" harvests are often stored for many years before being needed for transplant in a subsequent relapse. The effect of long-term cryostorage (5-14 years) on the viability and functional capacity of haematopoietic stem cells (HSCs) was investigated in 40 bone marrow and peripheral blood harvests using standard in vitro methods, the colony forming unit-granulocyte/macrophage (CFU-GM) assay and a single platform viable CD34(+) cell absolute count by flow cytometry. Forty percent of harvests had CD34(+) HSC counts of at least 0.7 x 10(6)/kg bodyweight and 85% had CFU-GM counts of at least 1.0 x 10(5)/kg bodyweight, these values representing our institutional minimum requirements for safe transplantation. Based on these results, it appears that HSC collections can remain adequate for safe transplantation after up to 14 years of cryostorage. However, as deterioration of HSC quality and viability may occur, some precautions may be warranted, namely harvesting higher than normal numbers of HSCs in collections intended for long-term storage and repeating in vitro assays on harvests after long-term storage prior to transplantation.