Predictors of Secondary Lung Cancer Among Hodgkin Lymphoma Survivors: A Nationwide Analysis.

PURPOSE: There is insufficient data regarding the incidence rate of secondary lung cancer among Hodgkin lymphoma (HL) survivors and the predisposing factors. METHODS: We analyzed the data from the cohort of patients who had HL between 1973 and 2015 using the Surveillance Epidemiology and End Results database (SEER). Data on patient's age, gender, year of diagnosis with HL, Ann-Arbor stage, Histology, racial groups, date of last follow-up, date of death, and treatment modalities were collected. RESULTS: We identified a total of 56,856 patients with HL; of those, 862 had secondary lung cancer, with an incidence rate of 157 (95%CI: 147-168) per 100,000 person-years. The median overall survival from time of HL diagnosis for those with secondary lung cancer was 12.1 years (95% CI: 10.7-13) compared to 27.1 years (95% CI: 26.5-27.6) for those who did not develop lung cancer (log-rank P-value of <.01). After propensity score weighting, radiation therapy was associated with a higher risk of secondary lung cancer (hazard ratio (HR): 1.23, 95% CI: 1.002-1.55) with a P-value of 0.048. Older age at the time of HL diagnosis and male gender were associated with higher risk, with an HR of 1.07 (95% CI 1.062-1.073) and an HR of 1.602 (95% CI 1.33-1.94), respectively. Furthermore, chemotherapy increased the risk only among older age groups. CONCLUSION: Older age at the time of HL diagnosis, male gender, radiation therapy, and chemotherapy only among older age groups were associated with higher risk for secondary lung cancer, with 50% of the cases occurring within 9.1 years following HL diagnosis.

Pim kinase inhibitor co-treatment decreases alternative non-homologous end-joining DNA repair and genomic instability induced by topoisomerase 2 inhibitors in cells with FLT3 internal tandem duplication.

Acute myeloid leukemia (AML) with fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) relapses with new chromosome abnormalities following chemotherapy, implicating genomic instability. Error-prone alternative non-homologous end-joining (Alt-NHEJ) DNA double-strand break (DSB) repair is upregulated in FLT3-ITD-expresssing cells, driven by c-Myc. The serine/threonine kinase Pim-1 is upregulated downstream of FLT3-ITD, and inhibiting Pim increases topoisomerase 2 (TOP2) inhibitor chemotherapy drug induction of DNA DSBs and apoptosis. We hypothesized that Pim inhibition increases DNA DSBs by downregulating Alt-NHEJ, also decreasing genomic instability. Alt-NHEJ activity, measured with a green fluorescent reporter construct, increased in FLT3-ITD-transfected Ba/F3-ITD cells treated with TOP2 inhibitors, and this increase was abrogated by Pim kinase inhibitor AZD1208 co-treatment. TOP2 inhibitor and AZD1208 co-treatment downregulated cellular and nuclear expression of c-Myc and Alt-NHEJ repair pathway proteins DNA polymerase θ, DNA ligase 3 and XRCC1 in FLT3-ITD cell lines and AML patient blasts. ALT-NHEJ protein downregulation was preceded by c-Myc downregulation, inhibited by c-Myc overexpression and induced by c-Myc knockdown or inhibition. TOP2 inhibitor treatment increased chromosome breaks in metaphase spreads in FLT3-ITD-expressing cells, and AZD1208 co-treatment abrogated these increases. Thus Pim kinase inhibitor co-treatment both enhances TOP2 inhibitor cytotoxicity and decreases TOP2 inhibitor-induced genomic instability in cells with FLT3-ITD.

Is Hashimoto's thyroiditis a risk factor for medullary thyroid carcinoma? Our experience and a literature review.

The etiology of medullary thyroid carcinoma remains unknown. The aim of this study was to determine whether there is a significant association between medullary thyroid carcinoma and Hashimoto's thyroiditis in the histopathologic material of thyroidectomized patients. Retrospective cross-sectional study. In this study, we reviewed the medical records of all patients who underwent total thyroidectomy for different thyroid-related complaints between January 2000 and January 2012 at Jordan University Hospital-Amman, Jordan. To highlight relevant previously published studies addressing this topic, a literature search was conducted for English language studies reporting "medullary thyroid carcinoma" or "C-cell hyperplasia" in patients with Hashimoto's thyroiditis. Of the 863 patients with a mean age of 47.2 ± 12.3 years who underwent total thyroidectomy during the study period, 78 (9.04 %) were diagnosed with Hashimoto's thyroiditis, and 15 (1.74 %) had medullary thyroid carcinoma, 3 (20 %) of whom had coexistent Hashimoto's thyroiditis. A total of 683 (79.1 %) patients had benign thyroid disease, 67 (9.8 %) of whom had Hashimoto's thyroiditis. The difference between these rates was not statistically significant (p = 0.19). When examined by gender, 9 females had medullary thyroid carcinoma, 3 (33.3 %) of whom had coexistent Hashimoto's thyroiditis; by contrast, of 560 females with benign thyroid disease, 62 (11.1 %) had Hashimoto's thyroiditis (p = 0.04). Although this study population represents a small and single-institution experience, our results suggest that there might be an association between Hashimoto's thyroiditis and medullary thyroid carcinoma only in female patients who undergo total thyroidectomy.