Temozolomide pharmacodynamics in patients with metastatic melanoma: dna damage and activity of repair enzymes O6-alkylguanine alkyltransferase and poly(ADP-ribose) polymerase-1.

PURPOSE: Temozolomide, a DNA methylating agent used to treat melanoma, induces DNA damage, which is repaired by O6-alkylguanine alkyltransferase (ATase) and poly(ADP-ribose) polymerase-1 (PARP-1)-dependent base excision repair. The current study was done to define the effect of temozolomide on DNA integrity and relevant repair enzymes as a prelude to a phase I trial of the combination of temozolomide with a PARP inhibitor. EXPERIMENTAL DESIGN: Temozolomide (200 mg/m2 oral administration) was given to 12 patients with metastatic malignant melanoma. Peripheral blood lymphocytes (PBL) were analyzed for PARP activity, DNA single-strand breakage, ATase levels, and DNA methylation. PARP activity was also measured in tumor biopsies from 9 of 12 patients and in PBLs from healthy volunteers. RESULTS: Temozolomide pharmacokinetics were consistent with previous reports. Temozolomide therapy caused a substantial and sustained elevation of N7-methylguanine levels, a modest and sustained reduction in ATase activity, and a modest and transient increase in DNA strand breaks and PARP activity in PBLs. PARP-1 activity in tumor homogenates was variable (828 +/- 599 pmol PAR monomer/mg protein) and was not consistently affected by temozolomide treatment. CONCLUSIONS: The effect of temozolomide reported here are consistent with those documented in previous studies with temozolomide and similar drug, dacarbazine, demonstrating that a representative patient population was investigated. Furthermore, PARP activity was not inhibited by temozolomide treatment and this newly validated pharmacodynamic assay is therefore suitable for use in a proof-of-principle phase I trial a PARP-1 inhibitor in combination with temozolomide.     

Phase II study of low-dose decitabine in patients with chronic myelogenous leukemia resistant to imatinib mesylate.

PURPOSE: To determine the activity of decitabine, a DNA methylation inhibitor, in imatinib-refractory or intolerant chronic myelogenous leukemia. MATERIALS AND METHODS: Thirty-five patients were enrolled in this phase II study (12 in chronic phase, 17 in accelerated phase, and six in blastic phase). Decitabine was administered at 15 mg/m2 intravenously over 1 hour daily, 5 days a week for 2 weeks. DNA methylation was measured using a LINE1 bisulfite/pyrosequencing assay. RESULTS: Complete hematologic responses were seen in 12 patients (34%) and partial hematologic responses in seven patients (20%), for an overall hematologic response rate of 54% (83% in chronic phase, 41% in accelerated phase, and 34% in blastic phase). Major cytogenetic responses were observed in six patients (17%), and minor cytogenetic responses were seen in 10 patients (29%) for an overall cytogenetic response rate of 46%. Median response duration was 3.5 months (range, 2 to 13+ months). Myelosuppression was the major adverse effect, with neutropenic fever in 28 (23%) of 124 courses of therapy. LINE1 methylation decreased from 71.3% +/- 1.4% (mean +/- standard error of the mean) to 60.7% +/- 1.4% after 1 week, 50.9% +/- 2.4% after 2 weeks, and returned to 66.5% +/- 2.7% at recovery of counts (median, 46 days). LINE1 methylation at the end of week 1 did not correlate with subsequent responses. However, at day 12, the absolute decrease in methylation was 14.5% +/- 3.0% versus 26.8% +/- 2.7% in responders versus nonresponders (P = .007). CONCLUSION: Decitabine induces hypomethylation and has clinical activity in imatinib refractory chronic myelogenous leukemia. We hypothesize that the inverse correlation between hypomethylation 2 weeks after therapy and response is due to a cell death mechanism of response, whereby resistant cells can withstand more hypomethylation.     

Crack and cocaine use among female prostitutes in Glasgow: Risky business

The experience of cocaine and 'crack' use among participants involved in (n = 19) or exiting (n = 10) prostitution in Glasgow, Scotland, is described. In-depth semi-structured qualitative interviews enquired about their use and experience of using cocaine and their perception of its effect on working practice. Twenty-three of 29 participants had used cocaine and 15 out of 29 had used crack cocaine. In reality, freebase not 'crack' was being self-manufactured from cocaine powder. Participants considered that cocaine use in the city was not restricted to prostitution but was reflected throughout the drug scene generally. One possible reason suggested for this was a perceived reduction in heroin availability at a time when cocaine was increasingly readily available. There was no evidence from participants to suggest that they were first introduced to cocaine through prostitution. Most participants believed that using cocaine did not affect how they worked, however they perceived that other prostitutes were prepared to take more risks to support their cocaine use and had to work longer hours to finance a cocaine habit compared to financing a heroin habit. Only participants recruited from the east end of the city spoke about their desperation for money and the sexual risks that they were prepared to take to buy cocaine. Harm-reduction messages should address the sexual and personal risks that some female prostitutes may be taking to support their cocaine use. Treatment and support services in the city, traditionally established to work with problematic heroin users, need to adapt to the changing drug trends among female drug users, including those involved in prostitution, and offer appropriate treatment options and harm-reduction advice to cocaine users.     

A NOTCH1 gene copy number gain is a prognostic indicator of worse survival and a predictive biomarker to a Notch1 targeting antibody in colorectal cancer

Dysregulation of the Notch1 receptor has been shown to facilitate the development and progression of colorectal cancer (CRC) and has been identified as an independent predictor of disease progression and worse survival. Although mutations in the NOTCH1 receptor have not been described in CRC, we have previously discovered a NOTCH1 gene copy number gain in a portion of CRC tumor samples. Here, we demonstrated that a NOTCH1 gene copy number gain is significantly associated with worse survival and a high percentage of gene duplication in a cohort of patients with advanced CRC. In our CRC patient‐derived tumor xenograft (PDTX) model, tumors harboring a NOTCH1 gain exhibited significant elevation of the Notch1 receptor, JAG1 ligand and cleaved Notch1 activity. In addition, a significant association was identified between a gain in NOTCH1 gene copy number and sensitivity to a Notch1‐targeting antibody. These findings suggest that patients with metastatic CRC that harbor a gain in NOTCH1 gene copy number have worse survival and that targeting this patient population with a Notch1 antibody may yield improved outcomes.     

Lack of effect of aprepitant on the pharmacokinetics of docetaxel in cancer patients

Background Aprepitant is a selective neurokinin-1 receptor antagonist that is effective for the prevention of nausea and vomiting caused by highly emetogenic chemotherapy. In vitro, aprepitant is a moderate inhibitor of the CYP3A4 enzyme, which is involved in the clearance of several chemotherapeutic agents. In this study we examined the potential for aprepitant to affect the pharmacokinetics and toxicity of intravenously administered docetaxel, a chemotherapeutic agent that is primarily metabolized by CYP3A4.Methods A total of 11 cancer patients (4 male, 7 female, aged 50–68 years) were enrolled in this multicenter, randomized, open-label, two-period, crossover study. Patients received a single infusion of docetaxel monotherapy, 60–100 mg/m², on two occasions at least 3 weeks apart. During one of the cycles (treatment A), patients received docetaxel alone. During the alternate cycle (treatment B), they also received aprepitant 125 mg orally 1 h prior to docetaxel infusion (day 1), and a single oral dose of aprepitant 80 mg on days 2 and 3. The pharmacokinetic profile of docetaxel was assessed over 30 h following docetaxel infusion. Blood counts were monitored on days 1, 4, 7, and 14.Results Ten patients completed the study. Concomitant administration of aprepitant did not cause any statistically or clinically significant changes in docetaxel pharmacokinetics. Values for docetaxel alone (treatment A) versus docetaxel with aprepitant (treatment B) were as follows: geometric mean AUC_0–last was 3.26 vs 3.17 g h/ml (P>0.25; ratio B/A 0.97); geometric mean AUC_0– 3.51 vs 3.39 g h/ml (P>0.25; ratio B/A 0.96); geometric mean C_max was 3.53 vs 3.37 g/ml (P>0.25; ratio B/A 0.95); and geometric mean plasma clearance was 23.3 vs 24.2 l/h/m² (P>0.25; ratio B/A 1.04). The corresponding harmonic mean half-life values were 10.1 and 8.5 h. The two treatment regimens had similar tolerability profiles; the median absolute neutrophil count nadirs were 681/mm³ during treatment with docetaxel alone and 975/mm³ during aprepitant coadministration.Conclusions Aprepitant had no clinically significant effect on either the pharmacokinetics or toxicity of standard doses of docetaxel in cancer patients. Aprepitant at clinically recommended doses may have a low potential to affect the pharmacokinetics of intravenous chemotherapeutic agents metabolized by CYP3A4.     

Serum creatinine to absolute lymphocyte count ratio effectively risk stratifies patients who require intensive care in hospitalized patients with coronavirus disease 2019

Patients with preexisting kidney disease or acute kidney injury had poorer outcomes in coronavirus disease 2019 (COVID-19) illness. Lymphopenia was associated with more severe illness. Risk stratification with simple laboratory tests may help appropriate site patients in a cost-effective manner and ease the burden on healthcare systems. We examined a ratio of serum creatinine level to absolute lymphocyte count at presentation (creatinine-lymphocyte ratio, CLR) in predicting outcomes in hospitalized patients with COVID-19. We analyzed 553 consecutive polymerase chain reaction-positive SARS-COV-2 hospitalized patients. Patients with end-stage kidney disease were excluded. Serum creatinine and full blood count (FBC) examination were obtained within the first day of admission. We examined the utility of CLR in predicting adverse clinical outcomes (requiring intensive care, mechanical ventilation, acute kidney injury requiring renal replacement therapy or death). An optimized cutoff of CLR > 77 was derived for predicting adverse outcomes (72.2% sensitivity, and 83.9% specificity). Ninety-seven patients (17.5%) fell within this cut off. These patients were older and more likely to have chronic medical conditions. A higher proportion of these patients had adverse outcomes (13.4% vs 1.1%, P < .001). On receiver operating curve analyses, CLR predicted patients who had adverse outcomes well (area under curve [AUC] = 0.82, 95%CI 0.72–0.92), which was comparable to other laboratory tests like serum ferritin, C-reactive protein and lactate dehydrogenase. Elevated CLR on admission, which may be determined by relatively simple laboratory tests, was able to reasonably discriminate patients who had experienced adverse outcomes during their hospital stay. This may be a simple and cost-effective means of risk stratification and triage.