CHARIOT: a phase I study of berzosertib with chemoradiotherapy in oesophageal and other solid cancers using time to event continual reassessment method.

BACKGROUND: Berzosertib (M6620) is a highly potent (IC50 = 19 nM) and selective, first-in-class ataxia telangiectasia-mutated and Rad3-related protein kinase (ATR) inhibitor. This trial assessed the safety, preliminary efficacy, and tolerance of berzosertib in oesophageal cancer (A1 cohort) with RT and advanced solid tumours (A2 cohort) with cisplatin and capecitabine. METHODS: Single-arm, open-label dose-escalation (Time-to-Event Continual Reassessment Method) trial with 16 patients in A1 and 18 in A2. A1 tested six dose levels of berzosertib with RT (35 Gy over 15 fractions in 3 weeks). RESULTS: No dose-limiting toxicities (DLTs) in A1. Eight grade 3 treatment-related AEs occurred in five patients, with rash being the most common. The highest dose (240 mg/m2) was determined as the recommended phase II dose (RP2D) for A1. Seven DLTs in two patients in A2. The RP2D of berzosertib was 140 mg/m2 once weekly. The most common grade ≥3 treatment-related AEs were neutropenia and thrombocytopenia. No treatment-related deaths were reported. CONCLUSIONS: Berzosertib combined with RT is feasible and well tolerated in oesophageal cancer patients at high palliative doses. Berzosertib with cisplatin and capecitabine was well tolerated in advanced cancer. Further investigation is warranted in a phase 2 setting. CLINICAL TRIALS IDENTIFIER: EU Clinical Trials Register (EudraCT) - 2015-003965-27 ClinicalTrials.gov - NCT03641547.

Determinants of outcome in melanoma patients with cerebral metastases.

PURPOSE: To analyze prognostic factors, effects of treatment, and survival for patients with cerebral metastases from melanoma. PATIENTS AND METHODS: All melanoma patients with cerebral metastases treated at the Sydney Melanoma Unit between 1952 and 2000 were identified. From 1985 to 2000, patients were diagnosed and treated using consistent modern techniques and this cohort was analyzed in detail. Multivariate analysis of prognostic factors for survival was performed. RESULTS: A total of 1137 patients with cerebral metastases were identified; 686 were treated between 1985 and 2000. For these 686 patients, the median time from primary diagnosis to cerebral metastasis was 3.1 years (range, 0 to 41 years). A total of 646 patients (94%) have died as a result of melanoma. The median survival from the time of diagnosis of cerebral metastasis was 4.1 months (range, 0 to 17.2 years). Treatment was as follows: surgery and postoperative radiotherapy, 158 patients; surgery alone, 47 patients; radiotherapy alone, 236 patients; and supportive care alone, 210 patients. Median survival according to treatment received for these four groups was 8.9, 8.7, 3.4, and 2.1 months, respectively; the differences between surgery and nonsurgery groups were statistically significant. On multivariate analysis, significant factors associated with improved survival were surgical treatment (P <.0001), no concurrent extracerebral metastases (P <.0001), younger age (P =.0007), and longer disease-free interval (P =.036). Prognostic factors analysis confirmed the important influence of patient selection on treatment received. CONCLUSION: This large series documents the characteristics of patients who developed cerebral metastases from melanoma. Median survival was dependent on treatment, which in turn was dependent on patient selection.

The spontaneous and evoked release of spermine from rat brain in vitro.

1 The efflux of previously accumulated [3H]-spermine from brain slices was measured using a continuous perfusion system. The spontaneous efflux was biphasic, consisting of an initial rapid efflux followed by a much slower release. 2 The slices were depolarized by the addition to the medium of high potassium concentrations, ouabain or veratrine. 3 At concentrations greater than 30 mM, potassium evoked a striking increase in the release of [3H]-spermine. Following uptake in the presence of 5.7 x 10(-9)M [3H]-spermine, K+-evoked release was dependent on the presence of calcium ions. Release of spermine after uptake at 5.6 x 10(-8)M or 5.0 x 10(-7)M was not calcium-dependent. 4 The calcium-dependent, K+-stimulated release of spermine was inhibited in the presence of diphenylhydantoin (5 x 10(-5)M) or ruthenium red (10(-5)M). 5 Following uptake of 5.7 x 10(-9)M [3H]-spermine in a sodium-free medium, the calcium-dependent, K+-stimulated release was significantly inhibited. 5 Ouabain (10(-4)M) caused a large but calcium-independent increase in the efflux of [3H]-spermine. 7 Veratrine-induced release was less substantial but was increased in a calcium-free medium. Release evoked by veratrine was abolished in the absence of sodium. 8 These results are discussed with respect to a possible 'neurotransmitter' or 'neuromodulator' role for spermine.

Susceptibility of ovarian granulosa cells to apoptosis differs in cells isolated before or after the preovulatory LH surge.

The luteinizing hormone (LH) surge initiates the final stages of ovarian follicle development, and induces ovulation and luteinization of preovulatory follicles. To investigate whether exposure to the LH surge alters follicle cell susceptibility to apoptosis, granulosa and theca cells were isolated from bovine preovulatory follicles before and 14 h after injection of GnRH to induce an LH surge. Granulosa cells isolated before the LH surge were susceptible to apoptosis induced by soluble Fas ligand or serum withdrawal, while cells isolated after the LH surge were resistant to apoptosis. Resistance to Fas-mediated apoptosis was not associated with decreased Fas mRNA or protein levels. Pretreatment of granulosa cells isolated after the LH surge with the protein synthesis inhibitor cycloheximide rendered the cells susceptible to Fas-mediated apoptosis, indicating that inhibition of apoptosis was mediated by expression of labile survival factors. Theca cells were sensitive to Fas-mediated apoptosis before and after exposure to the LH surge. Resistance to apoptosis of granulosa cells from preovulatory follicles after the LH surge may be important for normal ovulation and luteinization.

Use of Lilium longiflorum, cv. ace pollen germination and tube elongation as a bioassay for the hepatocarcinogens, aflatoxins.

Although various animal tissues are used for bioassay of aflatoxins (B1, B2, G1, G2), a rapid bioassay dependent upon a plant part's response does not exist. Both pollen germination (G) and tube elongation (TE) were enhanced in a 3.0 mM KH2PO4 (K)-containing but AFB1-lacking, modified Dickinson's medium. The B1 did not affect G when K was withheld but K supplementation impaired G above 15 micrograms/ml B1. Without K, 5-20 stimulated but 25 and 30 micrograms/ml B1 inhibited TE which was suppressed by every B1 conc tested in K-containing medium. Addition of NaH2PO4(N) instead of K to medium did not promote G. Slight G stimulation occurred at 16.6 micrograms/ml mixed aflatoxins (MA) in medium lacking either K or N but low G inhibitions were observed with K or N. The MA at 33.3 micrograms/ml reduced G 2.5% in K's of N's absence and 26 or 17% in their presence. While K did not stimulate TE without MA, N did 26%. At 16.6 and 33.3 micrograms/ml MA, TE was reduced 19, 6, 19% and 24, 25, 31%, respectively, in control, K- and N- media. Pollen G and TE were markedly sensitive to G1. Significant inhibitions of Zea mays seed G were observed at 5.8 and 11.6 micrograms/ml B1 but not root elongation (RE) from 0.4-11.6 micrograms/ml. The MA (31.5 micrograms/ml) administered for 72-240 hr did not influence either Arachis hypogeae seed G or RE. However, imbibing 5 cultivars each of Avena sativa (65-117 hr) and Hordeum vulgare (39-89 hr) inhibited RE 4/15-62%. Thus, except for Z. mays, pollen G and TE appear to be more B1-sensitive than seed G and RE. But, the pollen bioassay is less sensitive than both certain animal bioassays (0.025 micrograms/ml) and analytical methodologies (10 pg.).

Systemic nodular panniculitis with cardiac involvement.

A case of systemic nodular panniculitis is described in which the myocardium was found at necropsy to be extensively involved with focal interstitial carditis, identical histologically with nodules of panniculitis biopsied from the skin. This degree of myocardial involvement, which was not apparent during life and was not confined to pericardial or myocardial adipose tissue, has not previously been reported. The literature relating to nodular panniculitis is briefly reviewed and the concept of Weber-Christian disease critically re-appraised.

Reoperative parathyroid surgery in the era of sestamibi scanning and intraoperative parathyroid hormone monitoring.

HYPOTHESIS: Results of reoperative parathyroid surgery (RPS) have improved with the advent of sestamibi parathyroid subtraction scanning and intraoperative parathyroid hormone (IOPTH) monitoring. DESIGN: Retrospective review of patient histories, preoperative localization studies, operative data, including IOPTH monitoring, and outcomes for patients undergoing recent RPS at a single institution. Follow-up was complete (mean, 20 months). SETTING: Tertiary care referral center. PATIENTS: All patients undergoing RPS for benign persistent or recurrent primary hyperparathyroidism during the period 1989 to 1997. MAIN OUTCOME MEASURES: Overall cure rate and operative morbidity from RPS; sensitivity and accuracy of preoperative localization studies; and prediction of cure from IOPTH monitoring. RESULTS: The study group included 124 patients (87 women and 37 men). Hypercalcemia was corrected in 109 patients (88%). Permanent recurrent laryngeal nerve injury occurred in 0.8% and permanent hypoparathyroidism in 13% of patients. Test sensitivities and accuracies, respectively, were as follows: ultrasound with biopsy, 90% and 82%; sestamibi parathyroid subtraction scanning, 82% and 67%; and ultrasound alone, 75% and 65%. Level of IOPTH was predictive of cure in all patients with a 70% or greater fall from baseline at 20 minutes after excision. Persistent multigland disease was the major cause for reoperative failure (73%). CONCLUSIONS: Neither cure rates nor operative morbidity have changed appreciably over the past 2 decades, despite the introduction of sestamibi parathyroid subtraction scanning and IOPTH monitoring. Multigland disease continues to represent the principal cause of failure in RPS despite the routine use of preoperative localization studies. Thus far, increasing the stringency of IOPTH monitoring from a 50% to 70% decline from baseline levels has been predictive of cure, even in multigland disease. Most missed abnormal glands reside in normal anatomic locations, and the need for multiple operations, not just the reoperation, results in the increased morbidity seen with RPS.

Effect of gonadotropin-releasing hormone on fertility in repeat-breeder California dairy cows.

To assess the potential benefit to fertility from gonadotropin-releasing hormone (GnRH) administration to third service cows managed in typical California dairy systems, 963 cows were enlisted from 14 dairies served by 6 veterinary practices. The cows were randomly assigned to receive either GnRH (100 mug) or placebo at the time of the third artificial insemination. Fertility data were entered onto a proprietary microcomputer program common to all six practices, and collated independently by a third party. For the duration of the trial (1 yr), GnRH and placebo-treated cows had 43.2 and 39.3% conception rates, respectively (P=0.35). When treatments administered in summer months (July, August, September) were excluded, conception rates were 48.1 and 41.0%, respectively (P<0.1). The conception rates of cows treated with GnRH in August tended to be lower than those of placebo-treated cows (95% logarithmic confidence intervals of odds ratio = -1.139, 0.377). Between-herd variation in benefit from GnRH was evident, with two dairies showing no benefit, one dairy showing a negative effect, and four showing a range of effects from lightly beneficial to significantly beneficial. First-lactation cows did not benefit at any time from GnRH treatment. The data suggest that GnRH administered to third-service dairy cows under California conditions may result in increased conception rates in non-summer months, but that other unidentified variables may have important influence on the outcome of such treatment.

Pathogen inactivation of Leishmania donovani infantum in plasma and platelet concentrates using riboflavin and ultraviolet light.

BACKGROUND AND OBJECTIVES: Leishmania is transmitted by the bite of the phlebotomine sandfly or by transfusion of infected blood products. Leishmaniasis currently poses a significant problem in several parts of the world, and is an emerging problem in others. The Mirasol PRT technology is based on the use of riboflavin and ultraviolet light to generate chemical reactions in the nucleic acids of pathogens, which prevents replication and leads to inactivation. The intent of this study was to examine the ability of the Mirasol PRT System to kill the Leishmania parasite in human plasma and platelet concentrates. MATERIALS AND METHODS: In visceral Leishmaniasis, amastigotes are present in the blood and in the reticuloendothelial system within monocytes. For each unit of plasma or platelets treated, isolated mononuclear cells obtained from 100 ml of normal donor whole blood were incubated with 1.0 x 10(8) Leishmania donovani infantum promastigotes to produce amastigote-laden macrophages. The infected macrophages were added to 250 ml of human plasma or to 250 ml of platelet concentrates. Infected units were cultured pretreatment in 10-fold serial dilutions to determine the limits of detection. Thirty millilitres of 500 microM riboflavin was added to each unit, which was then illuminated with 5.9 J/cm2 of ultraviolet light (6.24 J/ml). After treatment and after 2 months of frozen storage, plasma units were cultured in 10-fold serial dilutions. Platelets were cultured on the day of treatment and on day 5 of storage post-illumination. RESULTS: A 5 log reduction of Leishmania was demonstrated in five of six units of plasma, and a 7 log reduction of Leishmania was demonstrated in one plasma unit. A 5 log reduction of Leishmania was demonstrated in five of six units of platelets, and a 6 log reduction of Leishmania was demonstrated in one unit. CONCLUSIONS: There is no donor screen for Leishmania and other pathogens constantly emerging in our blood supply. The Mirasol PRT System for Platelets and Plasma is an effective means of killing Leishmania and other emerging pathogens in these blood products.

Activities of contemporary Mayan elders.

Social gerontology researchers have investigated various aspects of elder activities in diverse culture contexts. This project assessed the knowledge that Mayan people have about the activities of their elders. Data were collected through two interview procedures. The first procedure, free-listing, was conducted with an initial sample of Mayan subjects (n=31), who provided terms representing their cultural knowledge of elder Mayan activities. A second sample (n=56) performed a pile sort task using 18 of those activities. The pile sort findings were subjected to multidimensional scaling, and that technique produced a two-dimensional visual representation of three distinct clusters of activities: productive work, serious socio-religious undertakings and frivolous ventures. Besides the coherent multidimensional scaling representation for that total sample of 56 subjects, scalings for subsamples based on generational affiliation were run. Two-dimensional pictures or visual maps for the aged, middle-aged and young adult subjects are remarkably similar to each other and to the picture for the total sample. From a methodological perspective the research findings demonstrate that elder Mayan activities, and presumably those of elders in other societies, are amenable to interview procedures that have high validity and high reliability.

Surgical treatment of painful lichen planus of the hand and foot.

Lichen planus of the hands and feet, although uncommon, can be very disabling with painful hypertrophic areas or ulcers, mainly of palmar and plantar surfaces. These lesions may not respond to conventional medical treatment. A case of surgical treatment with excision and split skin grafting of ulcerative lichen planus of the soles, with a fourteen year follow up, is reported. Only three other reported cases with a longer review period could be found. A second patient is described in which excision and grafting of painful, hypertrophic, ulcerative lichen planus of the hands achieved a satisfactory long term outcome. No other examples could be found in the English literature. It is suggested that surgical treatment should be considered more often and sooner in painful lichen planus of the hands and feet.

Cutaneous anaesthesia in necrobiosis lipoidica.

Cutaneous sensation in plaques of necrobiosis lipoidica was assessed in five non-diabetic and seven diabetic patients. Eleven of the twelve showed partial or complete anaesthesia of the affected skin. These findings are important in the differential diagnosis of tuberculoid leprosy. Further studies of nerve function in cutaneous granulomas need to be carried out.

High-affinity uptake of spermine by slices of rat cerebral cortex.

The accumulation of the polyamine spermine into 0.1-mm prisms of rat cerebral cortex has been investigated at both 37 percent C and at 4 percent C. Kinetic analysis of the temperature-sensitive portion of uptake indicates two high-affinity saturable components together with an unsaturable component at high concentrations. The "very high'-affinity saturable system (K(m)= 3.8 nM) was temperature- and sodium-dependent, and significantly reduced by metabolic inhibitors, finding that are consistent with an active transport system for spermine into brain tissue. The "high'-affinity saturable component (K(m)= 0.44 micron) was sodium-dependent and inhibited by ouabain, but only partially susceptible to inhibition by 2,4-dinitrophenol and sodium cyanide. The significance of these results with respect to the function of spermine in the central nervous system is discussed.

Milk recorder dermatitis.

Occupational contact dermatitis to Bronopol and Kathon CG has been identified in 3 milk recorders following the introduction of a new milk preservative. The source of exposure, sensitising potential and measures for prevention are discussed.