Faculty Bibliography

Introduction: The JAK2^V617F mutation accounts for most cases of myeloproliferative neoplasms (MPN). Only a few case reports of MPN following cytotoxic chemotherapy have been reported, and all of them were published prior to the discovery of the JAK2 ^V617F mutation. We report a series of 6 patients who developed a JAK2 ^V617F positive MPN following cytotoxic chemotherapy. Patients: From 2006 to 2009, 6 patients with a history of a hematologic or an oncologic malignancy who developed an MPN were identified and their medical records retrospectively reviewed. One patient had acute lymphoblastic leukemia, 1 had Hodgkin lymphoma, 1 had squamous cell carcinoma of the head and neck, 1 had cervical cancer, and 2 had breast cancer. All patients were in remission from their primary malignancies at the time the MPN was diagnosed. Five were females. The median age at diagnosis was 72 years. Median time to development of the myeloproliferative neoplasm was 14 years. Type of chemotherapy exposure, MPN diagnosis and time to MPN in each case is shown in the table below. The JAK2 ^V617F mutation was detected either in the peripheral blood or the bone marrow of all patients. There was no predominance of any specific MPN diagnosis. Patients who received platinum-based chemotherapy developed the MPN sooner than those who received alkylators (6 vs 17.5 years respectively). Treatment consisted of phlebotomy, hydroxyurea, anagrelide, aspirin or a combination as deemed appropriate by the treating hematologist. Conclusion: These findings lead us to hypothesize whether the development of JAK2 ^V617F positive MPN may be related to prior exposure to cytotoxic chemotherapy. Exposure to platinum-based chemotherapy may cause the disorder to appear sooner compared with exposure to alkylators. Recently, JAK2 ^V617F positive MPN was found to be strongly associated with a specific constitutional haplotype, 46/1¹ suggesting increased susceptibility to this mutation. Chromosomal analyses are planned to show whether any of the reported patients exhibit this haplotype.(Table presented)

Introduction: Quantifying cellularity is an integral component of bone marrow examinations. Estimates of marrow cellularity may influence the diagnostic interpretation of bone marrow samples. The accuracy of cellularity estimates may be influenced by the variable distribution of cellular elements within the marrow space. To better understand the degree of heterogeneity of bone marrow cellularity, we undertook a study to quantify the variable distribution of bone marrow cells in bone marrow core biopsies. Method: 8 gauge bone marrow core biopsies of 20 patients were retrospectively reviewed by 2 hematopathologists (SI,CL). The specimens were recovered from the posterior superior iliac crest using standard technique with 8G Snarecoil biopsy needles by 3 operators (KH, PK, GD). The percent cellularity was determined in sequential 0.2 X 0.4 cm portions of the core biopsies by each of the hematopathologists. Cellularities were recorded in 10% increments. Results: The mean age of the patients was 73.2 1.8 years. There were 12 males and 8 females. 5 patients had monoclonal gammopathies. Anemia, multiple myeloma and thrombocytopenia were each diagnosed in three patients. 2 patients demonstrated myelodysplasia and 1 patient each had acute leukemia, leukocytosis, non-Hodgkin's lymphoma and thrombocytosis. The mean white blood cell count, hemoglobin and platelet count were 8.7 (range 3.842.8), 12.2 (range 10.115.3), and 233 (range 91226), respectively. The mean length of the core biopsies was 1.78 0.09 cm (range 1.43.3) and the median number of 0.2 x 0.4 cm portions examined per core biopsy was 8 (range 512). In total, 165 portions were examined by each hematopathologist independently. The cellularity of 12 and 11 portions could not be determined by each of the hematopathologists, respectively, as a result of biopsy artifacts. No core biopsy showed a consistent cellularity within the examined portions, each core demonstrating a range of cellularities. Only 2/20 and 1/20 of the core biopsies, as examined by each hematopathologist, respectively, demonstrated 2 consistent cellularities. A median of 4 different cellularities were identified in each core. The mean range of cellularities of each core's portions was 43 4.6 %, and 46.5 4.9 %, as determined by the 2 hematopathologists, respectively, which was statistically equivalent (paired t-test p=0.349)

Topoisomerase-1 is a key sub-cellular target for anti-cancer therapy. This intranuclear enzyme, responsible for DNA replication and repair, undergoes interaction with camptothecin and several semi-synthetic camptothecin analogs to produce cell-death. Preclinical studies on the mechanism of action and metabolism of these drugs are reviewed. Clinical activity including phases I-III studies is reviewed for topotecan (FDA approved for the indications of ovarian and small-cell lung cancers) and irinotecan (approved for colon cancer and non-small-cell lung cancer). Activity in numerous other settings is reviewed for these approved agents. Other topoisomerase-1 inhibitors currently being tested in the clinic including 9-amino and 9-nitro camptothecin, exatecan, lurtotecan and edotecarin are reviewed for both preclinical rationale and clinical trials. Topoisomerase-1 inhibition is a validated approach to cancer treatment and remains an area of active drug development