Molecular assessment of pretransplant chemotherapy in the treatment of juvenile myelomonocytic leukemia.

BACKGROUND: Despite the intensity of hematopoietic stem cell transplantation (HCT), relapse remains the most common cause of death in juvenile myelomonocytic leukemia (JMML). In contrast to other leukemias where therapy is used to reduce leukemic burden prior to transplant, many patients with JMML proceed directly to HCT with active disease. The objective of this study was to elucidate whether pre-HCT therapy has an effect on the molecular burden of disease and how this affects outcome post-HCT. PROCEDURE: Twenty-one patients with JMML who received pre-HCT therapy and were transplanted at UCSF were analyzed in this study. The mutant allele frequency of the driver mutation was assessed before and after pre-HCT therapy, using custom amplicon next-generation sequencing. RESULTS: Of the 21 patients, seven patients (33%) responded to therapy with a significant reduction in their mutant allele frequency and were classified as molecular responders. Six of these patients received moderate-intensity chemotherapy, one patient received only azacitidine. The 5-year progression-free survival after HCT of molecular responders was 100% versus 61% for nonresponders (P = .12). Survival of molecular nonresponders was not improved by use of high-intensity conditioning, but patients were salvaged if they experienced severe graft versus host disease. There were no baseline clinical characteristics that were associated with response to pre-HCT therapy. CONCLUSIONS: Despite the myelodysplastic nature of JMML, patients treated with pre-HCT therapy can achieve molecular remissions. These patients experienced a trend toward improved outcomes post-HCT. Importantly, molecular testing can be helpful to distinguish between responders and nonresponders and should become an integral part of clinical care.

Chemesthetic responses to airborne mineral dusts: boric acid compared to alkaline materials.

OBJECTIVES: (1) To assess the relation between occupationally relevant exposures to dust of boric acid and magnitude of feel in the eye, nose, and throat during activity (pedaling) equal to light industrial work. (2) To compare feel from the dust of boric acid with that of the alkaline dusts calcium oxide and sodium tetraborate pentahydrate (sodium borate). (3) To chart how magnitude of feel changes with time in exposures up to 3/4 h. METHODS: Twelve subjects, six males and six females, participated in duplicate sessions of exposure to 2.5, 5, and 10 mg m(-3) of boric acid, 10 mg m(-3) of sodium borate, 2.5 mg m(-3) of calcium oxide presented as calcium oxide alone or diluted with hydrated calcium sulfate, and 0 mg m(-3) (blank). Exposures occurred in a plastic dome suspended over the head and closed around the neck with rubber dam. Measurements pre- and post-exposure included nasal secretion and nasal resistance. Measurements during exposure included rated magnitude of feel in the eye, nose, and throat, and respiration (Respitrace System). Six concentrations of carbon dioxide ranging from just below detectable to sharply stinging gave subjects references for their ratings. RESULTS: In general, feel increased for periods up to half an hour, then either declined or held at a plateau. Each material had a temporal signature. The nose led with the highest feel, followed by the throat, then the eyes. This hierarchy proved weakest for boric acid; at one level of exposure, magnitude in the throat overtook that in the nose. Accompanying measures implied that change of feel with time occurred neither because of an increase in dilution of the dissolved dusts in newly secreted mucus nor an increase of consequence in nasal resistance. Most likely, sensory adaptation determined the change. Boric acid of 10 mg m(-3) fell slightly and insignificantly below 10 mg m(-3) sodium borate in feel. Boric acid, though, showed a relatively flat dose-response relationship, i.e., a change in level caused little change in feel. CONCLUSIONS: The time-constant for feel from dusts lies on the order of tens of minutes. A flat concentration-response function for boric acid and a notable response from the throat suggests that perceived dryness, not mediated by acidity but perhaps by osmotic pressure, may account for the feel evoked at levels of exposure at or below 10 mg m(-3). More acidic dusts that could actually change nasal pH may trigger sensations differently.

Sensory and associated reactions to mineral dusts: sodium borate, calcium oxide, and calcium sulfate.

Occupational exposure limits (OELs) for irritant dusts have had no quantifiable bases. This study (1) charted chemosensory feel, denoted chemesthesis here, to dusts of calcium oxide (1 to 5 mg/m(3)), sodium tetraborate pentahydrate [sodium borate] (5 to 40 mg/m(3)), and calcium sulfate (10 to 40 mg/m(3)); (2) examined correlates of the chemesthetic sensations; and (3) sought to illuminate the basis for potency. Twelve screened men exercised against a light load while they breathed air in a dome fed with controlled levels of dust for 20 min. Measured parameters included nasal resistance, nasal secretion, minute ventilation, heart rate, blood oxygenation, mucociliary transport time, and chemesthetic magnitude, calibrated to pungency of carbon dioxide. Subjects registered time-dependent feel from exposures principally in the nose, secondarily in the throat, and hardly in the eyes. Calcium oxide had the greatest potency, followed by sodium borate, with calcium sulfate a distant third. Of the physiological parameters, amount of secretion showed the best association with chemesthetic potency. That measure, as well as mucociliary transport time and minute ventilation, went into calculation of mass of dust dissolved into mucus. The calculations indicated that the two alkaline dusts increased in equal molar amounts with time. At equal molar concentrations, they had, to a first approximation, equal chemesthetic magnitude. On the basis of mass concentration in air or dissolved into mucus, calcium oxide and sodium borate differed in potency by a factor just above five, equal to the difference in their molecular weights. This relationship could inform the setting of OELs for a critical effect of irritation.