The pharmacokinetics, metabolism, and excretion of aromatically labeled tritiated vincristine (VCR) was examined in 4 patients. Clearance of radioactivity from the blood was triphasic with half-life t1/2 values of 0.85, 7.4, and 164 min. The initial phases probably represent distribution and binding to formed blood elements which exceeded 50% of the administered dose by 20 min. Excretion of radioactivity was principally fecal, with 33% recovered in the feces by 24 hr and 69% by 72 hr. Considerably less radioactivity (12%) was excreted in the urine over the 72-hr period. Approximately 40% of fecally excreted and 46% of urinary excreted radiolabel represented metabolites, which suggests that at least 34% of the VCR dose was excreted as metabolies. Plasma metabolites represented from less than 1% to 30% or more of radioactivity in plasma. Ultraviolet spectral analysis of all metabolites revealed preservation of the intact VCR dimer, which suggests that metabolism involves alteration of side groups.
While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04 – 1.15, p = 1.9 x 10−4 (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03 – 1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted pinteraction values > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients’ survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.
The current algorithm for Lynch syndrome diagnosis is highly complex with multiple steps which can result in an extended time to diagnosis while depleting precious tumor specimens. Here we describe the analytical validation of a custom probe-based NGS tumor panel, TumorNext-Lynch-MMR, which generates a comprehensive genetic profile of both germline and somatic mutations that can accelerate and streamline the time to diagnosis and preserve specimen. TumorNext-Lynch-MMR can detect single nucleotide variants, small insertions and deletions in 39 genes that are frequently mutated in Lynch syndrome and colorectal cancer. Moreover, the panel provides microsatellite instability status and detects loss of heterozygosity in the five Lynch genes; MSH2, MSH6, MLH1, PMS2 and EPCAM. Clinical cases are described that highlight the assays ability to differentiate between somatic and germline mutations, precisely classify variants and resolve discordant cases.
Two patients with acute lymphoblastic leukemia treated on the same protocol became blind during complete remission. Therapy consisted of systemic combination chemotherapy, prophylactic central nervous system irradiation and monthly intrathecal cytosine arabinoside. Eight months after CNS irradiation visual acuity in both patients began to decrease. Meningeal leukemia in the area of the chiasm was suspected but despite additional radiotherapy, steroids and continued intrathecal therapy, both patients were blind within 6 months. Numerous lumbar punctures were negative for leukemic cells. Extensive investigation, including craniotomy in one case, failed to reveal the cause of blindness. Biopsy of the optic nerve in one case was compatible with radiation toxicity. We postulate that potentiation of radiation toxicity to the optic nerves and chiasm by systemic chemotherapy, intrathecal chemotherapy, or both, may have led to blindness. The patients continue in complete hematologic and CNS remission 12 and 29 months after becoming blind.Cancer 39:58-61, 1977.EUROLOGIC AND OPTHALMOLOGIC COMPLICA-N tions of leukemia have been ascribed both to t h e disease2~12*1r a n d to t h e toxicity of therapy. 136*7*10*16Blindness is a n unusual complication of leukemia a n d generally portends a poor prognosis. I2e1' T h e present report describes two patients with acute lymphoblastic leukemia (ALL) w h o developed total visual loss i n the absence of demonstrable central nervous system leukemia. Both patients received combination systemic chemotherapy in addition t o prophylactic central nervous system treatment with cranial irradiation and intrathecal cytosine arabinoside. Blindness occurred a s a complication during complete remission. CASE REPORTS Case 1A 2 Y2-year-old girl developed ALL in May, 1972. She presented with a hemoglobin of 6.4 g/lOO ml, a white blood cell count of 6,000/mma and a platelet count of 24,000/mma. Bone marrow aspirate was Received for publication April 9, 1976. hypercellular with 90% lymphoblasts. Treatment was begun on protocol 72-1 of the Pediatric Oncology Branch. Following four courses of POMP induction therapy, consisting of prednisone (1000 mg/mz I.V. days 1-5), vincristine [2.0 mg/ma I.V. day 1 (man. 2 mg)] methotrexate (7.5 mg/mz I.V. days 1-5), 6 mercaptopurine (125 mg/mZ I.V. days 1-S), and allopurinol (100 mg/m2 I.V. T.I.D.), a bone marrow remission was achieved. Consolidation therapy was then begun. Total brain irradiation, with shielding of the eyes, was given over a three week period to a total dose of 2400 rads (200 rads per day for 12 days). Intrathecal Cytosine Arabinoside (30 mg/ma) was administered four times in each of the first 2 weeks of radiotherapy. With each lumbar puncture the patient received an oral dose of hydroxyurea (1.5 gms/m2). Also, five day courses of vincristine, methotrexate and prednisone were given during the first and third weeks of radiotherapy at the sme dosage levels used during induction therapy. Consolidation therapy was concluded with two courses of Cytosine ...
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