A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias.

BACKGROUND: Ponatinib is a potent oral tyrosine kinase inhibitor of unmutated and mutated BCR-ABL, including BCR-ABL with the tyrosine kinase inhibitor-refractory threonine-to-isoleucine mutation at position 315 (T315I). We conducted a phase 2 trial of ponatinib in patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL). METHODS: We enrolled 449 heavily pretreated patients who had CML or Ph-positive ALL with resistance to or unacceptable side effects from dasatinib or nilotinib or who had the BCR-ABL T315I mutation. Ponatinib was administered at an initial dose of 45 mg once daily. The median follow-up was 15 months. RESULTS: Among 267 patients with chronic-phase CML, 56% had a major cytogenetic response (51% of patients with resistance to or unacceptable side effects from dasatinib or nilotinib and 70% of patients with the T315I mutation), 46% had a complete cytogenetic response (40% and 66% in the two subgroups, respectively), and 34% had a major molecular response (27% and 56% in the two subgroups, respectively). Responses were observed regardless of the baseline BCR-ABL kinase domain mutation status and were durable; the estimated rate of a sustained major cytogenetic response of at least 12 months was 91%. No single BCR-ABL mutation conferring resistance to ponatinib was detected. Among 83 patients with accelerated-phase CML, 55% had a major hematologic response and 39% had a major cytogenetic response. Among 62 patients with blast-phase CML, 31% had a major hematologic response and 23% had a major cytogenetic response. Among 32 patients with Ph-positive ALL, 41% had a major hematologic response and 47% had a major cytogenetic response. Common adverse events were thrombocytopenia (in 37% of patients), rash (in 34%), dry skin (in 32%), and abdominal pain (in 22%). Serious arterial thrombotic events were observed in 9% of patients; these events were considered to be treatment-related in 3%. A total of 12% of patients discontinued treatment because of an adverse event. CONCLUSIONS: Ponatinib had significant antileukemic activity across categories of disease stage and mutation status. (Funded by Ariad Pharmaceuticals and others; PACE ClinicalTrials.gov number, NCT01207440 .).

A normally masked nuclear matrix antigen that appears at mitosis on cytoskeleton filaments adjoining chromosomes, centrioles, and midbodies.

mAbs were generated against HeLa nuclear matrix proteins and one, HIB2, which selectively stained mitotic cells, was selected for further study. Western blot analysis showed H1B2 antibody detected a protein of 240 kD in the nuclear matrix fractions. The H1B2 antigen was completely masked in immunofluorescently stained interphase cells. However, removing chromatin with DNase I digestion and 0.25 M ammonium sulfate extraction exposed the protein epitope. The resulting fluorescence pattern was bright, highly punctate, and entirely nuclear. Further extraction of the nuclear matrix with 2 M NaCl uncovers an underlying, anastomosing network of 9-13 nm core filaments. Most of the H1B2 antigen was retained in the fibrogranular masses enmeshed in the core filament network and not in the filaments themselves. The H1B2 antigen showed remarkable behavior at mitosis. As cells approached prophase the antigen became unmasked to immunofluorescent staining without the removal of chromatin. First appearing as a bright spot, the antibody staining spread through the nucleus finally concentrating in the region around the condensed chromosomes. The antibody also brightly stained the spindle poles and, more weakly, in a punctate pattern in the cytoskeleton around the spindle. As the chromosomes separated at anaphase, H1B2 remained with the separating daughter sets of chromosomes. The H1B2 antigen returned to the reforming nucleus at telophase, but left a bright staining region in the midbody. Immunoelectron microscopy of resinless sections showed that, in the mitotic cell, the H1B2 antibody did not stain chromosomes and centrioles themselves, but decorated a fibrogranular network surrounding and connected to the chromosomes and a fibrogranular structure surrounding the centriole.

A new technique for securing a foley catheter.

We describe a new technique to secure a urethral catheter using a horizontal drain tube stabilizer. This device is reliable, inexpensive, and more comfortable for patients than either adhesive tape or leg straps.

A phase I trial of oral ridaforolimus (AP23573; MK-8669) in combination with bevacizumab for patients with advanced cancers.

AIMS: This phase I dose-escalation study was designed to evaluate the combination of the mammalian target of rapamycin inhibitor ridaforolimus with the vascular endothelial growth factor inhibitor bevacizumab. MATERIALS AND METHODS: Seventeen adult patients with refractory advanced solid tumours received oral ridaforolimus (30 or 40 mg) once daily for 5 days per week (QDx5/wk) combined with intravenous bevacizumab (10 mg/kg every 2 weeks [Q2wk] or 15 mg/kg every 3 weeks [Q3wk]). Patients were evaluated for dose-limiting toxicities, safety and anti-tumour activity. RESULTS: A 40 mg dose of ridaforolimus with either bevacizumab dosing schedule was the recommended phase II dose. No dose-limiting toxicities were reported; the most common drug-related adverse events were mucosal inflammation and anorexia. Seven patients, with clinical features that included primary tumour of the abdominal origin (colorectal, pancreatic or gynaecological cancers) and previous abdominal radiotherapy, reported serious adverse events related to bowel perforations. There were no objective responses, but 65% of patients had a best response of stable disease. CONCLUSION: Oral ridaforolimus (40 mg QDx5/wk) is feasible to combine with standard doses of bevacizumab, although careful patient selection would be needed to mitigate the risk of bowel perforation-related adverse events. Combination therapy produced prolonged stable disease in several heavily pretreated patients.

Moyamoya following cranial irradiation for primary brain tumors in children.

OBJECTIVE: To study the risk factors for the development of moyamoya syndrome after cranial irradiation for primary brain tumors in children. METHODS: We reviewed neuroimaging studies and dosimetry data for 456 children who were treated with radiation for a primary brain tumor and who were prospectively evaluated with serial neuroimaging studies and neurologic evaluations. A total of 345 patients had both adequate neuroimaging and radiation dosimetry data for further analysis. We used survival analysis techniques to examine the relationship of clinically important variables as risk factors for the development of moyamoya over time. RESULTS: Overall, 12 patients (3.5%) developed evidence of moyamoya. The onset of moyamoya was more rapid for patients with neurofibromatosis type 1 (NF1) (median of 38 vs 55 months) and for patients who received >5,000 cGy of radiation (median of 42 vs 67 months). In a multiple Cox proportional hazards regression analysis controlling for age at start of radiation, each 100-cGy increase in radiation dose increased the rate of moyamoya by 7% (hazard ratio [HR] = 1.07, 95% CI: 1.02 to 1.13, p = 0.01) and the presence of NF1 increased the rate of moyamoya threefold (HR = 3.07, 95% CI: 0.90 to 10.46, p = 0.07). CONCLUSIONS: Moyamoya syndrome is a potentially serious complication of cranial irradiation in children, particularly for those patients with tumors in close proximity to the circle of Willis, such as optic pathway glioma. Patients who received higher doses of radiation to the circle of Willis and with neurofibromatosis type 1 have increased risk of the development of moyamoya syndrome.

Improved patient positioning for percutaneous nephroscopic procedures using a surgical saddle.

PURPOSE: We describe modified patient positioning on the Cloward surgical saddle for use during percutaneous nephroscopic procedures. MATERIALS AND METHODS: The Cloward surgical saddle, which was designed for prone patient positioning, has been used primarily for lumbar surgery. We evaluated the use of the surgical saddle for ease of patient positioning during percutaneous nephroscopic procedures. RESULTS: We have used the surgical saddle in 10 patients to date, including 1 who was 5 feet 8 inches (173 cm.) tall and who weighed 370 pounds (168 kg.). In all cases pulmonary airway pressure was maintained at less than 30 cm. water. We have observed no incidence of pressure injury or other complications associated with position. CONCLUSIONS: Patient positioning during percutaneous nephroscopic surgery is important for preventing pressure injury and allowing adequate pulmonary ventilation. The surgical saddle is an excellent aid for secure patient positioning during percutaneous nephroscopic procedures that helps to minimize the risk of pressure injury and pulmonary compromise.

Prenatal diagnosis of alobar holoprosencephaly at 10 weeks of gestation.

Alobar holoprosencephaly is an intracranial abnormality characterized by failure of proper cleavage of the prosencephalon, accompanied by incomplete midfacial development. The prenatal sonographic diagnosis of alobar holoprosencephaly was first described in 1984; however, there have been only two reports of alobar holoprosencephaly diagnosed in the first trimester. We report a case of alobar holoprosencephaly diagnosed at 10 weeks of gestation.

Dorsal band traction for reduction of paraphimosis.

Reduction of paraphimosis can be a painful and difficult process. Methods thus far proposed focus on decreasing the edema before reduction. We have used the basic surgical principle of traction and countertraction by applying a pair of Adson forceps directly to the band formed by the retracted preputial opening. To date we have successfully used this technique on 6 children and 3 adults.

Basal cell carcinoma originating from a nevus sebaceus on the scalp of a 7-year-old boy.

Basal cell carcinoma (BCC) occurs rarely in children and is most often associated with an underlying condition that predisposes patients to the development of malignancy. There have been numerous reports of BCC developing after puberty in nevus sebaceus; however, such occurrences have rarely been described in children. We report a 7-year-old boy with BCC forming in a nevus sebaceus.

Differences in iodinated peptides and thyroid hormone formation after chemical and thyroid peroxidase-catalyzed iodination of human thyroglobulin.

The distribution of iodine among the polypeptides of human goiter thyroglobulin (Tg) was examined. Tg was iodinated in vitro with 131I to levels of 2 to 84 gram atoms (g.a.)/mol using thyroid peroxidase (TPO) or a chemical iodination system. The samples were reduced, alkylated, and subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Two low-molecular-weight peptides appeared preferentially in radioautograms of the sodium dodecyl sulfate (SDS) gels of TPO-iodinated samples. Iodination of these peptides increased sharply in the TPO-treated Tg as the level of total iodine/molecule rose. Radioiodine was incorporated into these same gel regions in the chemically treated Tg, but only after much higher levels of total iodination were reached. Differences in iodoamino acid distribution were also noted between the chemically and enzymatically iodinated thyroglobulins. In the chemically iodinated samples, little thyroxine (T4) was synthesized, even at high iodine levels. In the TPO-treated samples only small amounts of T4 were seen below 14 g.a. total I/mol, while at or above that level of iodination T4 formation increased sharply. To examine the coupling process, Tg was chemically iodinated, excess I- removed, and the samples treated with TPO and a H2O2-generating system in the absence of iodide. Radioautograms obtained from SDS-polyacrylamide gels of reduced and alkylated protein from such coupling assays showed an increase in the level of iodine in the low-molecular-weight peptides after TPO treatment. Thyroxine production also increased with TPO treatment. The addition of free DIT (a known coupling enhancer) to the [131I]Tg/TPO incubation increased both the production of T4 and the amount of iodine in the smaller polypeptides. Two-dimensional maps prepared from CNBr-digested TG showed differences between the coupled and uncoupled samples. Our observations confirm the importance of the low-molecular-weight peptides derived from Tg in thyroid hormone synthesis. At total iodine levels above 14 g.a./mol Tg in enzymatically treated samples there is selective incorporation of iodine into both the low-molecular-weight polypeptides and into thyroid hormone.

Use of novel urodynamic parameters, detrusor contraction duration and detrusor contraction index, in men with lower urinary tract symptoms.

The aim of this study was to correlate the results of the urodynamic measures, detrusor contraction duration (DCD) and detrusor contraction index (DCI), with voiding symptoms in untreated men with lower urinary tract symptoms (LUTS) and in men treated with doxazosin. Ninety-one men with untreated LUTS underwent urodynamic evaluation. DCD (duration of detrusor contraction in seconds), DCI (interval, in seconds, that urine is passed divided by the total duration of the bladder contraction), and standard urodynamic measures of obstruction were determined. The urodynamic findings were correlated with the severity of voiding symptoms as assessed by the International Prostate Symptom Score (I-PSS). Fifty of these men were treated subsequently with 4 mg of doxazosin for 3 months and then underwent repeat urodynamic evaluation, in which changes in symptom score and urodynamic results were analyzed. DCD was the only urodynamic measure that correlated significantly with the I-PSS results in untreated patients. Although DCD, detrusor pressure at maximum flow, and the Abrams-Griffiths number decreased in men treated with doxazosin, only DCI and symptom score improved significantly after treatment for 3 months. No urodynamic parameter was useful in predicting the likelihood of a favorable response to treatment with doxazosin. DCD and DCI may be useful urodynamic measures in untreated men with LUTS and in those treated with doxazosin. Further study of these parameters is warranted.

The isolation of identical thyroxine containing amino acid sequences from bovine, ovine and porcine thyroglobulins.

Identical, thyroxine containing tryptic peptides have been isolated from digests of bovine, ovine and procine thyroglobulins. This 19 residue hormone containing sequence, NH2-Asn-Ile-Phe-Glu-T4-Gln-Val-Asp-Ala-Gln-Pro-Leu-Arg-Pro-Cys-Glu-Leu-G in-Arg- COOH, is completely conserved across these three species, and it represents a principal site of thyroxine synthesis. HPLC maps of tryptic digests of the thyroglobulins have been monitored at several wavelengths and suggest that, in each case, only a small number of tryptic peptides are iodinated in vivo and that an even smaller number of tryptic peptides contain thyroid hormone. These data are consistent with a high degree of selectivity in iodination of tyrosines within thyroglobulin and the subsequent coupling of these selected tyrosines to form thyroid hormone.

The Cuisinart food processor efficiently disaggregates tissues.

The Cuisinart Model DLC-7 PRO food processor efficiently disaggregates plant and animal tissues resulting in time savings and often increased yields in the isolated material.