First-in-human phase I study of the DNA-repair inhibitor DT01 in combination with radiotherapy in patients with skin metastases from melanoma.

BACKGROUND: DT01 is a DNA-repair inhibitor preventing recruitment of DNA-repair enzymes at damage sites. Safety, pharmacokinetics and preliminary efficacy through intratumoural and peritumoural injections of DT01 were evaluated in combination with radiotherapy in a first-in-human phase I trial in patients with unresectable skin metastases from melanoma. METHODS: Twenty-three patients were included and received radiotherapy (30 Gy in 10 sessions) on all selected tumour lesions, comprising of two lesions injected with DT01 three times a week during the 2 weeks of radiotherapy. DT01 dose levels of 16, 32, 48, 64 and 96 mg were used, in a 3+3 dose escalation design, with an expansion cohort at 96 mg. RESULTS: The median follow-up was 180 days. All patients were evaluable for safety and pharmacokinetics. No dose-limiting toxicity was observed and the maximum-tolerated dose was not reached. Most frequent adverse events were reversible grades 1 and 2 injection site reactions. Pharmacokinetic analyses demonstrated a systemic passage of DT01. Twenty-one patients were evaluable for efficacy on 76 lesions. Objective response was observed in 45 lesions (59%), including 23 complete responses (30%). CONCLUSIONS: Intratumoural and peritumoural DT01 in combination with radiotherapy is safe and pharmacokinetic analyses suggest a systemic passage of DT01.

To speak and be heard.

PIP: This article is excerpted from the Park Ridge Center for the Study of Health, Faith, and Ethics 28-page handbook entitled "Religion and Public Discourse: Principles and Guidelines for Religious Participants." These principles are the product of a three-year research project conducted by the Center. The project "To Speak and Be Heard" is based upon a wide range of resources from within the participants' religious traditions, including practices, rituals, and tenets of faith. While this project grew out of the specific controversies around the Cairo Conference, the principles of civil discourse spelled out in this document are general in application and may be used to facilitate constructive public dialogue. This article also discusses the nature of civil discourse in the public square, covenants of conversation, engaging the other, living with conflict during and after conversation and argument, and the hope of civil discourse.^ieng

Can we still hear the call? What it means to be Catholic.

Despite the drastic changes occurring in the world today, certain elements of the Catholic tradition and communion can make the transition into a world colored by merger and shaped by governmental concerns for the general, not the particular. If Catholic particularism to many degrees and in many ways has been lost, the "loss" occurred before, apart from, alongside, and in many ways independent of merger and governmental contexts. "We gave it away." These are days for retrieval. The Catholic response to "the call" has been complicated by the following forces: bureaucratization of the world, acceptance of the terms of a liberal (i.e., "open") society, pluralism, and governmental involvement. These factors are formidable, and they do change contexts for response to the call. But they need not stifle the response. The following are some of the elements in "the call" that the Catholic "we" can hear and respond to, while they are also graspable and transmittable by non-Catholics in merged, governmentally related institutions and associations: Catholicholism, concern for the soul, a sacramental view, attention to human dignity, the quest for meaning, the value of ritual, human exemplarity, responsibility to community, the call to justice, and a special ethos. This sampling of elements could be debated within Catholic and in pluralistic contexts. But rather than debate, I would picture a value in conversation in each institution, system, association, or network. This conversation involves Catholics and non-Catholics alike.

Phase I and pharmacokinetic study of the camptothecin derivative irinotecan, administered on a weekly schedule in cancer patients.

Irinotecan (CPT-11) is a novel water-soluble, semisynthetic derivative of camptothecin, with inhibitory effects on mammalian DNA topoisomerase I, high cytotoxic activity in vitro and anticancer activity in animal models. Fifty-nine patients, with cancer refractory to conventional therapy, were entered in this phase I study, using a weekly schedule administration. A total of 304 weekly doses were administered at dose levels ranging from 50 to 145 mg/m2 (30-90 min i.v. infusion). Leukoneutropenia and diarrhea were the dose-limiting toxicities and appeared to be dose related, reversible and noncumulative. However, interpatient variability of toxic effects was substantial. Prolongation of the infusion time from 30 min to 90 min appeared to decrease the diarrhea. Other toxicities included moderate emesis, asthenia, alopecia, abdominal pain, and anemia. CPT-11 plasma disposition was bi- or triphasic with a terminal half-life of 9.3 h. CPT-11 area under the plasma concentration versus time curves increased linearly with dose (r = 0.47, P < 0.01). The active metabolite area under the plasma concentration versus time curve correlated significantly with that of CPT-11, but not with that of CPT-11 dose. Both CPT-11 and 7-ethyl-10-hydroxycamptothecin areas under the plasma concentration versus time curve correlated significantly with leukoneutropenia and diarrhea. One partial and 4 minor responses were observed at dose levels of 130 and 145 mg/m2. Using this weekly schedule, recommended doses for phase II studies are 100 mg/m2 in high risk patients and 115 mg/m2 in others.

Religion, theology, church, and bioethics.

Modern medical ethics developed in America after mid-century chiefly at theological schools, but discourse on bioethics soon moved to the pluralist-secular settings of the academy and the clinic, where it acquired a philosophical and intentionally non-religious cast. An effort was made, on the grounds of 'liberal culture' and 'late Enlightenment rationality' to find a framework for inquiry which aspired to the universal. Today, while that language persists, it coexists with, challenges, and is challenged by forms of ethical analysis and advocacy which take into consideration the 'thickness' of complicating narrative and reasoning based in the many religious traditions. It has become incumbent upon advocates of those traditions to propose 'publicly accessible' argument.