Response of sensitive and resistant IgM immunocytomas to cis-diamminedichloroplatinum(II) does not correlate with the platination level or with the formation or removal of DNA adducts

 An IgM immunocytoma cell line sensitive to cis-diamminedichloroplatinum(II) (CDDP) and a subline with acquired resistance were grown in LOU/M rats. In a previous study with such rats that had been treated with a high dose of CDDP (10 mg/kg) the tumors did not show differences in cellular platinum content or DNA-adduct levels, either immediately after treatment or 24 h later. Recently, this high dose was found to overcome resistance. Therefore, the study was repeated with a 10-fold lower dose (1 mg/kg, i.v.). At 1 and 24 h after treatment, tumor and kidney tissue were assayed for cellular platinum (atomic absorption spectroscopy, AAS) and DNA platination (immunochemical detection of the four CDDP-DNA adducts). The results were compared with previous data. All tissues showed a linear response to dose with regard to platinum uptake as well as adduct formation, with no quantitative difference being seen between the tumors. Also the relative occurrence of the four adducts was very similar. Between 1 and 24 h, in tumors a substantial decrease occurred in both platinum content and adduct level; the kidneys showed little reduction, if any. At the lower CDDP dose a somewhat larger loss of platinum and removal of DNA adducts was observed for the resistant tumor, but these differences could be explained by “dilution”, as this tumor continues to grow after low-dose treatment (about 20% within 24 h). Since the strong difference observed between the tumors in sensitivity to CDDP cannot be attributed to differences in CDDP uptake, efficiency of adduct formation, or repair capability, other mechanisms are held responsible. Received 10 August 1995 / Accepted: 14 August 1996     

Ventricular arrhythmia and torsade de pointe: Dose limiting toxicities of the MDR-modulator S9788 in a phase I trial

Background: S9788 is a triazineaminopiperidine derivative capable of reversing multidrug resistance (MDR) in vitro. In preclinical models S9788 was several fold more potent MDR inhibitor than verapamil or cyclosporine. At P-glycoprotein (Pgp) blocking concentrations, S9788 appeared to have only very little toxicity.Patients and methods: In a two step phase I trial we treated 39 patients with refractory cancer with S9788 and bolus doxorubicin. The steps differed mainly in the S9788 infusion duration; in the first part 23 patients received the MDR-reversing drug S9788 over 30 minutes, in the second step of the study 16 patients were administered S9788 over 150 minutes. The doses of S9788 were escalated in cohorts of three patients up to a dose level (DL) of 96 mg/m2 on the 30 minutes infusion, and to 144 mg/m2 on the 150 minutes infusion. The pharmacokinetics of S9788 were determined.Results: With the 30-minute infusion schedule symptomatic cardiac arrhythmia were found to be dose limiting. In all patients at the highest DL transient cardiac repolarization prolongation with a long QT-interval on ECG was demonstrated. With the 150-minute administration schedule, S9788 could be escalated up to 144 mg/m2 without subjective toxicity. However, transient QT prolongation was present in all patients. A third degree AV-block and a QT increase of about 40% occurred at the highest DL. Asymptomatic torsade de pointe (DL 96 mg/m2) was demonstrated on Holter recording in one patient. Theses repolarization disturbances with QT increase were considered dose limiting toxicity and the trial was closed. No arrhythmia related death was noted. Pharmacokinetics were similar with both infusion schedules with a mean alpha half life of 11.3 and 13.2 minutes, for the 30-minute and 150-minute infusion, and a terminal half life of 13.5 and 15 hours, respectively. QTc prolongation duration appeared to be dose-dependent.Conclusions: With the tested infusion schedules, cardiac toxicity, in particular AV-blocks and QT prolongation, leading to ventricular arrhythmia and torsade de pointe, are the dose limiting toxicities of S9788. Our experience together with the observation of asymptomatic torsade de pointe in two other phase I trials of S9788 infused over six hours precluded the further clinical development of S9788.     

Nocturnal O2 enrichment of room air at high altitude increases daytime O2 saturation without changing control of ventilation

In a randomized, double-blind study, 24 sea-level residents drove to 3,800-m altitude in 1 day, and then slept the first night in either ambient air or 24% oxygen, and the second night in the treatment that they did not receive on the first night. Oxygen enrichment, compared with ambient air, resulted in significantly fewer apneas, and significantly less time spent in periodic breathing during the night. The increase in SaO2 between evening and morning was significantly higher after sleeping in the oxygen-enriched atmosphere, compared with ambient air. However, this significant improvement in SaO2 did not persist into mid-day. The overnight treatment did not alter the ventilatory response to hypoxia or to carbon dioxide as measured the following morning. The results suggest that the elevation in SaO2 following overnight oxygen enrichment is probably not due to a change in the control of ventilation, but possibly to differences in subclinical lung pathology.     

Surgical complications and their management in a series of 300 consecutive pediatric cochlear implantations.

OBJECTIVE: To report the short- and long-term complications encountered in a large number of consecutive children undergoing implantation in a single center. The current study also describes the management and sequelae of each complication. STUDY DESIGN: Prospective study assessing the surgical findings and complications of deaf children undergoing implantation. SETTING: Pediatric tertiary referral center for cochlear implantation. PATIENTS: The present study includes 300 consecutive children undergoing implantation, with a mean age at implantation of 5.1 years, ranging from 1.3 to 16.9 years. Of these children, 196 (65%) had congenital deafness of unknown cause. The commonest known cause was meningitis (73 of 300 [24%]) followed by congenital cytomegalovirus infection (17 of 300 [6%]). Children have been followed up regularly after implantation, typically at yearly intervals after the first year. The mean duration of follow-up at the time of the study was 4 years (range, 0.1-14 yr). RESULTS: There were no major perioperative (within 1 d after surgery) or major early postoperative (within 1 wk after surgery) complications. In the same periods, there were 19 and 15 minor complications, respectively. These complications (e.g., eardrum perforation, hematoma, flap swelling, wound infection, temporary facial weakness) settled with conservative treatment or minor intervention. With regard to the late surgical complications (>1 wk after surgery), there were 7 major (e.g., severe flap infection requiring explantation, cholesteatoma, persistent eardrum perforation) and 14 minor complications (e.g., mild flap infection, flap swelling, hematoma). A number of complications were encountered even 14 years after the original operation, and some of them needed repeated interventions, highlighting the importance of long-term follow-up. However, most of the complications occurred very close to the surgical procedure (<1 yr). CONCLUSION: An overall rate of 2.3% for major surgical complications and an overall rate of 16% for minor surgical complications suggest that cochlear implantation is a relatively safe surgical operation in experienced centers. Most surgical complications are minor and can be managed with conservative treatment or minor surgical intervention. However, meticulous attention to surgical detail, especially handling soft tissues and leaving the posterior canal wall intact, and long-term follow-up are of paramount importance in minimizing the incidence of surgical complications.     

''I found myself to be a down to earth Dutch girl'': a qualitative study into learning outcomes from international traineeships

OBJECTIVE: To explore learning outcomes from international traineeships for undergraduate medical students. METHODS: In-depth interviews were conducted with 24 undergraduate medical students at Maastricht University Medical School, The Netherlands. The 24 subjects were selected by purposeful sampling. RESULTS: Students reported meaningful learning outcomes in 6 domains: medical knowledge; skills; international health care organisation; international medical education; society and culture, and personal growth. DISCUSSION: International traineeships appear to provide good opportunities for students to meet the requirements of globalisation as well as some of the generic objectives of undergraduate medical education. The tentative findings of this study need to be confirmed by further studies.     

Overexpression of the cytochrome p450 activator hpr6 (heme-1 domain protein/human progesterone receptor) in tumors.

OBJECTIVE: Hpr6 (heme-1 domain protein/human progesterone receptor) is one of a family of proteins that are implicated in progesterone metabolism, resistance to genotoxic agents and steroid biosynthesis. Because these processes are frequently misregulated in tumors, we have examined the expression of Hpr6 in a group of clinical tumor samples and cancer cell lines. METHODS: Hpr6 expression was analyzed by Western blot in extracts from breast, cervix, colon and thyroid cell lines and in nonmalignant and adjacent tumor tissue from breast, colon and thyroid. Hpr6 localization was determined by immunofluorescence. RESULTS: Hpr6 expression is significantly elevated in breast tumors in comparison with matched nonmalignant tissue and demonstrated limited overexpression in colon and thyroid tumors. Hpr6 is strongly expressed in a panel of tumor cell lines originating from breast, thyroid and colon. Hpr6 localizes to the perinuclear region of the cell, consistent with a role in cell detoxification, signaling and/or sterol synthesis. CONCLUSIONS: Hpr6 homologues regulate cytochrome P450 proteins implicated in hormone, steroid and xenobiotic chemical metabolism. These are the first studies linking Hpr6 expression to cancer progression and cellular survival. Our results suggest that Hpr6 is an important marker for cancer progression and a potential anticancer therapeutic target.