Phase I trial of the proteasome inhibitor bortezomib in patients with advanced solid tumors with observations in androgen-independent prostate cancer.

PURPOSE: To determine the dose-limiting toxicity and maximum-tolerated dose of the proteasome inhibitor bortezomib administered intravenously weekly for 4 every 5 weeks; to determine the bortezomib pharmacokinetics and pharmacodynamics using plasma levels and an assay for 20S proteasome inhibition (PI) in whole blood; to correlate toxicity with bortezomib dose and degree of 20S PI; and to conduct a preliminary determination of the antitumor activity of bortezomib in patients with androgen independent prostate cancer (AIPCa). PATIENTS AND METHODS: Fifty-three patients (48 with AIPCa) received 128 cycles of bortezomib in doses ranging from 0.13 to 2.0 mg/m(2)/dose, utilizing a careful escalation scheme with a continuous reassessment method. Pharmacokinetic and pharmacodynamic studies were performed in 24 patients (at 1.45 to 2.0 mg/m(2)). RESULTS: A dose-related 20S PI was seen, with dose-limiting toxicity at 2.0 mg/m(2) (diarrhea, hypotension) occurring at an average 1-hour post-dose of >/= 75% 20S PI. Other side effects were fatigue, hypertension, constipation, nausea, and vomiting. No relationship was seen between body-surface area and bortezomib clearance over the narrow dose range tested. There was evidence of biologic activity (decline in serum prostate-specific antigen and interleukin-6 levels) at >/= 50% 20S PI. Two patients with AIPCa had prostate-specific antigen response and two patients had partial response in lymph nodes. CONCLUSION: The maximum-tolerated dose and recommended phase II dose of bortezomib in this schedule is 1.6 mg/m(2). Biologic activity (inhibition of nuclear factor-kappa B-related markers) and antitumor activity is seen in AIPCa at tolerated doses of bortezomib. This agent should be further explored with chemotherapy agents in advanced prostate cancer.     

Empirically based recommendations to support parents facing the dilemma of paediatric cadaver organ donation.

The aim of the study was to describe the challenges donor and non-donor parents encounter before, during, and after the organ donation decision, and to identify parents' needs and expectations from health care professionals. A further aim was to propose evidence-based recommendations for effectively introducing the option of donation, and supporting families through the grieving process. This study was undertaken as part of a larger research project investigating the experiences of Greek parents who consented or declined organ and tissue donation, using a qualitative methodology for data collection and analysis. The experiences of 22 Greek bereaved parents of 14 underage brain dead children were studied through semi-structured interviews. Parents' decision-making process was described as challenging and fraught with difficulties both before and after the donation period. Identified challenges were clustered into: (a) personal challenges, (b) conditions of organ request, and (c) interpersonal challenges. Parents' main concern following donation was the lack of information about transplantation outcomes. Findings led to a list of recommendations for nurses and other health professionals for approaching and supporting parents in making choices about paediatric organ donation that are appropriate to them, and for facilitating their adjustment to the sudden death of their underage child.     

Intractable diarrhea of infancy with congenital intestinal mucosa abnormalities: outcome of four cases

Microvillous inclusion disease (MID) and epithelial dysplasia (ED) or tufting enteropathy are the most frequent causes of intractable diarrhea with persistent villous atrophy and indefinite dependence on total parenteral nutrition (PN) from early infancy. Since these are intractable diseases, they have been proposed to be elective indication for early bowel transplantation in order to avoid complications, such as PN-related liver disease, that would require a combined small bowel-liver transplant. We describe four cases of intractable diarrhea, two with MID and two with ED, seeking to discover whether these diseases are really elective, early indications for bowel transplant. Among our four patients, only one with ED underwent transplantation. The prognosis of small bowel transplant is still poor and worse than that of prolonged HPN. Further study is necessary to achieve a safe HPN program. Referral for transplant (small bowel only or combined with liver) should be considered when there is a venous access reduction and/or severe and irreversible liver disease.     

Thalidomide/estramustine/paclitaxel in metastatic androgen-independent prostate cancer

Background

This is a phase I/II trial of thalidomide with estramustine and paclitaxel in men with androgen-independent prostate cancer (AIPC) who underwent previous chemotherapy.

Patients and Methods

Men with progressive AIPC were treated with oral thalidomide (200 mg, 400 mg, or 600 mg daily), intravenous paclitaxel (100 mg/m² over 3 hours on days 3 and 10), and oral estramustine (140 mg 3 times daily on days 1-5 and days 8-12) every 21 days.

Results

Phase I: first cycle dose-limiting toxicity occurred in 0 of 3 patients at 200 mg thalidomide daily, 0 of 3 at 400 mg daily, and 1 of 3 at 600 mg daily (the designated maximum tolerated dose). Phase II: twenty-nine of 38 evaluable patients (76%; 95% confidence interval, 67%-87%) experienced a 50% decrease in prostate-specific antigen level. Five of 18 patients (28%) with measurable disease exhibited an objective response. Nine of 14 patients (64%) with disease refractory to previous taxane therapy had 50% decreases in prostate-specific antigen level. Grade 3/4 adverse events included neutropenia (9 of 39 [23%]), fatigue (9 of 39 [23%]), dyspnea (8 of 39 [21%]), and thromboembolic events (7 of 39 [18%]). Cumulative dose-limiting toxicity rates were minimal (13%) with thalidomide at 200 mg daily.

Conclusion

The profile of activity of thalidomide/paclitaxel/estramustine in taxane-refractory AIPC warrants further investigation.     

Real-Time PCR Assay for Rapid Detection of GSTM1 Polymorphism in Nasopharyngeal Carcinoma Patients

Nasopharyngeal carcinoma (NPC) is a common public health problem in Thailand. Glutathione S-transferaseM1 gene deletion (GSTM1 null genotype) carriers have been reported to be at increased risk and therefore thisparameter is a potential marker for screening of NPC high-risk individuals. However, the conventional polymerasechain reaction (C-PCR) assay commonly used for GSTM1 null genotype detection is not suitable for mass screeningsince it is inconvenient, time consuming and unsafe due to the use of a toxic chemical. Currently, real-time PCR(R-PCR) assay is recommended for quicker and safer detection of various genetic polymorphisms. The aim ofthis study was to develop a SYBR green I R-PCR assay combined with melting curve analysis for GSTM1polymorphism detection in Thai NPC patients. The results were compared to those from the C-PCR assay usingDNA samples from peripheral blood leukocytes of 120 Thai NPC patients. The frequencies of GSTM1polymorphism detected by the R-PCR and the C-PCR were the same. Forty-eight individuals that were GSTM1+in the R-PCR assay showed 2 peaks with melting points of 82.5˚C and 87.5˚C that correlated with the appearanceof 2 DNA bands in the C-PCR assay (i.e., one for GSTM1 at 215 base pairs (bp) and one for β-globin at 268 bp).By contrast, 72 individuals that were GSTM1- in the R-PCR assay showed 1 peak with a melting point of 87.5˚Cthat correlated with the appearance of 1 DNA band for β-globin at 268 bp in the C-PCR assay. The R-PCR assayusing SYBR Green I and melting curve analysis for GSTM1 polymorphism detection was as reliable as the CPCRassay but was quicker and safer and more amenable to large scale screening in Thai NPC cases.