https://www.nhlcyberfamily.org/tests/gene%20profiling%20diffuse.pdf

Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray

Background The incidence of hematologic cancers increases with age. These cancers are associated with recurrent somatic mutations in specific genes. We hypothesized that such mutations would be detectable in the blood of some persons who are not known to have hematologic disorders. Methods We analyzed whole-exome sequencing data from DNA in the peripheral-blood cells of 17,182 persons who were unselected for hematologic phenotypes. We looked for somatic mutations by identifying previously characterized single-nucleotide variants and small insertions or deletions in 160 genes that are recurrently mutated in hematologic cancers. The presence of mutations was analyzed for an association with hematologic phenotypes, survival, and cardiovascular events. Results Detectable somatic mutations were rare in persons younger than 40 years of age but rose appreciably in frequency with age. Among persons 70 to 79 years of age, 80 to 89 years of age, and 90 to 108 years of age, these clonal mutations were observed in 9.5% (219 of 2300 persons), 11.7% (37 of 317), and 18.4% (19 of 103), respectively. The majority of the variants occurred in three genes: DNMT3A, TET2, and ASXL1. The presence of a somatic mutation was associated with an increase in the risk of hematologic cancer (hazard ratio, 11.1; 95% confidence interval [CI], 3.9 to 32.6), an increase in all-cause mortality (hazard ratio, 1.4; 95% CI, 1.1 to 1.8), and increases in the risks of incident coronary heart disease (hazard ratio, 2.0; 95% CI, 1.2 to 3.4) and ischemic stroke (hazard ratio, 2.6; 95% CI, 1.4 to 4.8). Conclusions Age-related clonal hematopoiesis is a common condition that is associated with increases in the risk of hematologic cancer and in all-cause mortality, with the latter possibly due to an increased risk of cardiovascular disease. (Funded by the National Institutes of Health and others.)

/pdf/age-related-clonal-hematopoiesis-associated-with-adverse-1pxvez9t4c.pdf

Age-Related Clonal Hematopoiesis Associated with Adverse Outcomes

A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma study group

In a European BIOMED-2 collaborative study, multiplex PCR assays have successfully been developed and standardized for the detection of clonally rearranged immunoglobulin (Ig) and T-cell receptor (TCR) genes and the chromosome aberrations t(11;14) and t(14;18). This has resulted in 107 different primers in only 18 multiplex PCR tubes: three VH-JH, two DH-JH, two Ig kappa (IGK), one Ig lambda (IGL), three TCR beta (TCRB), two TCR gamma (TCRG), one TCR delta (TCRD), three BCL1-Ig heavy chain (IGH), and one BCL2-IGH. The PCR products of Ig/TCR genes can be analyzed for clonality assessment by heteroduplex analysis or GeneScanning. The detection rate of clonal rearrangements using the BIOMED-2 primer sets is unprecedentedly high. This is mainly based on the complementarity of the various BIOMED-2 tubes. In particular, combined application of IGH (VH-JH and DH-JH) and IGK tubes can detect virtually all clonal B-cell proliferations, even in B-cell malignancies with high levels of somatic mutations. The contribution of IGL gene rearrangements seems limited. Combined usage of the TCRB and TCRG tubes detects virtually all clonal T-cell populations, whereas the TCRD tube has added value in case of TCRgammadelta(+) T-cell proliferations. The BIOMED-2 multiplex tubes can now be used for diagnostic clonality studies as well as for the identification of PCR targets suitable for the detection of minimal residual disease.

Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: report of the BIOMED-2 Concerted Action BMH4-CT98-3936.

Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia.

We measured serum concentrations of immunoglobulin classes and IgG subclasses in 53 patients who had completed treatment for Hodgkin's disease and in 10 healthy adults. We wished to determine the relation of these classes and subclasses to the subjects' antibody responses to bacterial polysaccharide and viral protein antigens. Mean levels of the IgG-2 subclass were significantly lower in patients treated with both radiation and chemotherapy than in controls (P<0.05). The level of IgG-2 before immunization correlated directly with the mean antibody response both to 11 pneumococcal antigens (r = 0.71, P<0.001) and to the Haemophilus influenzae Type b antigen (r = 0.40, P<0.01). The correlation between IgG-2 concentration and pneumococcal antibody response was also significant in the 10 healthy adults (r = 0.70, P<0.05). The levels of no immunoglobulin class or subclass correlated significantly with antibody responses to influenza A/Victoria/75 and A/New Jersey/76 hemagglutinins, both of which are p...

https://www.nejm.org/doi/pdf/10.1056/NEJM198007243030402?listPDF=true

Correlation between Serum IgG-2 Concentrations and the Antibody Response to Bacterial Polysaccharide Antigens

Peripheral lymphocytes from 25 patients with chronic lymphocytic leukemia (CLL) and three with chronic lymphosarcoma-cell leukemia, and lymph-node cells from three of four with lymphocytic lymphoma bore on their cell surface IgM, which was readily demonstrated with fluorescein-conjugated antiserums. The lymphosarcoma cell differed from the cell of CLL in possessing much more surface immunoglobulin. Light-chain analysis of the surface IgM showed that cells bore either kappa or lambda determinants, but not both, indicating the clonal nature of these neoplasms. The serum of four leukemic patients was also found to contain small amounts of IgM M-components. Since the B lymphocyte (bone-marrow-derived) of laboratory animals bears large amounts of surface immunoglobulin and the T lymphocyte (thymus processed) does not, the findings favor the B-cell origin of these leukemic cells. A less likely possibility is that the CLL lymphocyte is a derepressed T cell.

Immunoglobulins on the surface of neoplastic lymphocytes.

BACKGROUND

Treatment-associated second neoplasms have emerged as a major threat to the continued survival of patients cured of Hodgkin's disease. In this study, the authors investigated the risk of breast carcinoma in an irradiated Hodgkin's disease population.



METHODS

One hundred and eleven women younger than 60 years presenting between 1964 and 1984 with Stage I and II Hodgkin's disease who received mantle irradiation were retrospectively analyzed and compared with an age specific population. Median follow-up was 18 years (range, 10-30 years), and the median age at initiation of therapy was 24 years. Kaplan-Meier actuarial risks, relative risks (RRs) (the ratio of the observed to the expected cases) with 95% confidence intervals (CIs), and the log rank test for trends were calculated.



RESULTS

Fourteen women developed breast carcinoma: 8 of 33 patients younger than 20 years at the time of irradiation, 5 of 48 patients age 20 to 29 years, and 1 of 30 patients age 30 years or older. Actuarial calculation predicted a 34.0% (CI, 14.2-53.8) risk of breast carcinoma at 25 years after therapy for the youngest group, 22.3% (CI, 4.1-40.5) for the group of intermediate age, and 3.5% (CI, 0-10.1) for the oldest group. The RR of breast carcinoma was 56 (CI, 23.3-107) for those 19 years or younger at the time of treatment, 7.0 (CI, 2.3-16.4) for those age 20-29 years, and 0.9 (CI, 0-5.3) for those 30 years and older. Excluding 1 patient who was age 38 years at the time of irradiation, the remaining 13 breast carcinomas were tightly clustered in women irradiated between the ages of 14 through 25, and were detected in years 11 through 25 after treatment, with 7 occurring in years 15 through 18.



CONCLUSIONS

Women younger than 30 years, particularly those younger than 20 years, who have received mantle irradiation for Hodgkin's disease require meticulous follow-up for breast carcinoma. The high incidence of breast carcinoma in this patient population should be considered when making treatment decisions in young women with early stage Hodgkin's disease. Cancer 1997; 79:1203-10. © 1997 American Cancer Society.

High risk of breast carcinoma after irradiation of young women with Hodgkin's disease

To determine if a normal antibody response can develop after therapy for Hodgkin's disease, we immunized 53 patients and 10 normal controls with dodecavalent pneumococcal vaccine. Antibody concentrations three weeks after immunization (geometric mean of 11 serotypes) were 1566 ng of protein nitrogen per milliliter in controls, 963 ng per milliliter after subtotal radiation (P<0.05 compared to controls), 658 ng per milliliter after chemotherapy (P<0.05), 377 ng per milliliter after subtotal radiation plus chemotherapy (P<0.01) and 283 ng per milliliter after total nodal radiation plus chemotherapy (P<0.001). Low levels of antibody before immunization correlated with a poor response (r = +0.73, P<0.001). The ability to respond to immunization improved significantly but did not return to normal as long as four years after combined therapy. The antibody response to pneumococcal vaccine is profoundly impaired in patients who have received intensive treatment for Hodgkin's disease: the ability of this ...

https://www.nejm.org/doi/pdf/10.1056/NEJM197808312990903?listPDF=true

Alan C. Aisenberg

Papers

Correlation between Serum IgG-2 Concentrations and the Antibody Response to Bacterial Polysaccharide Antigens

Immunoglobulins on the surface of neoplastic lymphocytes.

High risk of breast carcinoma after irradiation of young women with Hodgkin's disease

Impaired antibody response to pneumococcal vaccine after treatment for Hodgkin's disease.

T-cell chronic lymphocytic leukemia. Report of a case studied with monoclonal antibody.