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The PD-driven phase 0 trial is a new form, designed to be a first-in-man study, often of a new agent, conducted to assess drug effect on a molecular target, by means of a pharmacodynamic (PD) assay, in a very small number (10-15) of patients. Such a study is meant to be a proof of principle trial to determine whether the agent yields the PD effect predicted by pre-clinical studies. The dosage is meant to be pharmacologically active, but is neither toxic nor likely to yield clinical benefit. Such a trial may be used to serve as a very early test of an agent's biologic effect, allowing for early weeding out of ineffective agents, or as an early means of determining the most promising of competing analogue agents. This manuscript will present designs for such PD-driven studies that are statistically efficient and rigorous, focusing on non-comparative trials. The phase 0 trial promises to become an increasingly important tool for facilitating and speeding the development of new therapeutic agents, particularly in oncology.

This study aimed at characterizing the interspecies absorption, distribution, metabolism and elimination (ADME) profile of N-geranyl-N'-(2-adamantyl)ethane-1,2-diamine (SQ109), a new diamine-based antitubercular drug. Single doses of SQ109 were administered (intravenously (i.v.) and per os (p.o.)) to rodents and dogs and blood samples were analyzed by liquid chromatography tandem mass spectrometry (LC/MS/MS). Based on i.v. equivalent body surface area dose, the terminal half-life (t1/2) of SQ109 in dogs was longer than that in rodents, reflected by a larger volume of distribution (Vss) and a higher clearance rate of SQ109 in dogs, compared to that in rodents. The oral bioavailability of SQ109 in dogs, rats and mice were 2.4-5, 12 and 3.8%, respectively. After oral administration of [14C]SQ109 to rats, the highest level of radioactivity was in the liver, followed by the lung, spleen and kidney. Tissue-to-blood ratios of [14C]SQ109 were greater than 1. Fecal elimination of [14C]SQ109 accounted for 22.2% of the total dose of [14C]SQ109, while urinary excretion accounted for only 5.6%. The binding of [14C]SQ109 (0.1-2.5 microg ml-1) to plasma proteins varied from 6 to 23% depending on the species (human, mouse, rat and dog). SQ109 was metabolized by rat, mouse, dog and human liver microsomes, resulting in 22.8, 48.4, 50.8 or 58.3%, respectively, of SQ109 remaining after a 10-min incubation at 37 degrees C. The predominant metabolites in the human liver microsomes gave intense ion signals at 195, 347 and 363m/z, suggesting the oxidation, epoxidation and N-dealkylation of SQ109. P450 reaction phenotyping using recombinant cDNA-expressed human CYPs in conjunction with specific CYP inhibitors indicated that CYP2D6 and CYP2C19 were the predominant CYPs involved in SQ109 metabolism.

Background: To determine whether a delay in initiating external beam radiation therapy (RT) following diagnosis could impact prostate-specific antigen (PSA) outcome for patients with localized prostate cancer, 460 patients, who received 3D conformal RT to a median dose of 70.4 Gy for clinically localized prostate cancer between 1992 and 2001, were studied., Methods: The primary endpoint was PSA failure (American Society for Therapeutic Radiology and Oncology definition). Estimates of PSA control were made using the Kaplan-Meier method. Delay was defined as the time between diagnosis and the start of RT. Risk groups were defined based on known predictors of PSA outcome, namely, baseline PSA level, clinical T-category, Gleason score, and percentage of biopsy cores positive for tumor. Cox multivariate regression analysis was used to determine the ability of treatment delay to predict time to PSA failure after adjusting for the other known predictors., Results: Treatment delay independently predicted time to PSA failure following diagnosis for high-risk (Adjusted Hazard Ratio = 1.08 per month; P = 0.029) but not low-risk patients (P = 0.31). Patients with high-risk disease (n = 240) had 5-year estimates of PSA failure-free survival of 55% versus 39% (Plog-rank = 0.014) for those with delay < 2.5 months versus > or = 2.5 months respectively. The median delay was 2.5 months., Conclusions: Treatment delay adversely affected PSA outcome for high-risk patients but not for low-risk patients following RT.

SQ109 is a novel [1,2]-diamine-based ethambutol (EMB) analog developed from high-throughput combinatorial screening. The present study aimed at characterizing its pharmacodynamics and pharmacokinetics. The antimicrobial activity of SQ109 was confirmed in vitro (Mycobacterium tuberculosis-infected murine macrophages) and in vivo (M. tuberculosis-infected C57BL/6 mice) and compared to isoniazid (INH) and EMB. SQ109 showed potency and efficacy in inhibiting intracellular M. tuberculosis that was similar to INH, but superior to EMB. In vivo oral administration of SQ109 (0.1-25 mg kg(-1) day(-1)) to the mice for 28 days resulted in dose-dependent reductions of mycobacterial load in both spleen and lung comparable to that of EMB administered at 100 mg kg(-1) day(-1), but was less potent than INH at 25 mg kg(-1) day(-1). Monitoring of SQ109 levels in mouse tissues on days 1, 14 and 28 following 28-day oral administration (10 mg kg(-1) day(-1)) revealed that lungs and spleen contained the highest concentration of SQ109, at least 10 times above its MIC. Pharmacokinetic profiles of SQ109 in mice following a single administration showed its C(max) as 1038 (intravenous (i.v.)) and 135 ng ml(-1) (p.o.), with an oral T(max) of 0.31 h. The elimination t(1/2) of SQ109 was 3.5 (i.v.) and 5.2 h (p.o.). The oral bioavailability was 4%. However, SQ109 displayed a large volume of distribution into various tissues. The highest concentration of SQ109 was present in lung (>MIC), which was at least 120-fold (p.o.) and 180-fold (i.v.) higher than that in plasma. The next ranked tissues were spleen and kidney. SQ109 levels in most tissues after a single administration were significantly higher than that in blood. High tissue concentrations of SQ109 persisted for the observation period (10 h). This study demonstrated that SQ109 displays promising in vitro and in vivo antitubercular activity with favorable targeted tissue distribution properties.

Background: To the authors' knowledge, consensus is lacking regarding the relative long-term efficacy of radical prostatectomy (RP) versus conventional-dose external beam radiation therapy (RT) in the treatment of patients with clinically localized prostate carcinoma., Methods: A retrospective cohort study of 2635 men treated with RP (n = 2254) or conventional-dose RT (n = 381) between 1988-2000 was performed. The primary endpoint was prostate specific antigen (PSA) survival stratified by treatment received and high-risk, intermediate-risk, or low-risk group based on the serum PSA level, biopsy Gleason score, 1992 American Joint Commission on Cancer clinical tumor category, and percent positive prostate biopsies., Results: Estimates of 8-year PSA survival (95% confidence interval [95% CI]) for low-risk patients (T1c,T2a, a PSA level < or = 10 ng/mL, and a Gleason score < or = 6) were 88% (95% CI, 85, 90) versus 78% (95% CI, 72, 83) for RP versus patients treated with RT, respectively. Eight-year estimates of PSA survival also favored RP for intermediate-risk patients (T2b or Gleason score 7 or a PSA level > 10 and < or = 20 ng/mL) with < 34% positive prostate biopsies, being 79% (95% CI, 73, 85) versus 65% (95% CI, 58, 72), respectively. Estimates of PSA survival in high-risk (T2c or PSA level > 20 ng/mL or Gleason score > or = 8) and intermediate-risk patients with at least 34% positive prostate biopsies initially favored RT, but were not significantly different after 8 years., Conclusions: Intermediate-risk and low-risk patients with a low biopsy tumor volume who were treated with RP appeared to fare significantly better compared with patients who were treated using conventional-dose RT. Intermediate-risk and high-risk patients with a high biopsy tumor volume who were treated with RP or RT had long-term estimates of PSA survival that were not found to be significantly different., (Copyright 2002 American Cancer Society.DOI 10.1002/cncr.10657)

Background: Early (< or = 2 years) prostate specific antigen (PSA) failure after radical prostatectomy (RP) has been shown to predict for distant failure. After excluding patients with the pathologic predictors of early PSA failure, an analysis of PSA failure free (bNED) survival was performed to identify patients who may benefit from the use of postprostatectomy radiation therapy (RT)., Methods: Of 1,028 patients treated with RP for clinically localized prostate carcinoma between 1989 and 1999, 862 (84%) had either organ confined (OC), specimen confined (SC), or margin positive disease with negative seminal vesicles (SV) and a prostatectomy Gleason score < or = 7. A Cox regression multivariate analysis was performed in these patients evaluating the ability of the extent of extracapsular extension (ECE) (into but not through the capsule, SC focal ECE, SC established ECE, margin positive) and prostatectomy Gleason score (2-6 vs. 7) to predict time to postoperative PSA failure., Results: SC focal ECE (P = 0.0017), SC established ECE (P < 0.0001), and margin positive disease (P < 0.0001) were significant predictors of time to postoperative PSA failure, whereas prostatectomy Gleason score and disease extending into but not through the capsule were not. Five-year bNED rates were 90%, 88%, 69%, 45%, and 33% for patients with OC, into but not through capsule, SC focal ECE, SC established ECE, and margin positive prostate carcinoma, respectively., Conclusions: Patients with SC ECE or margin positive prostate carcinoma and a prostatectomy Gleason score < or = 7 with no evidence of SV invasion may benefit from adjuvant postoperative RT.

Background: A clinical staging system for localized prostate carcinoma that provides reliable information on which management decisions regarding an individual patient can be based is lacking. This study compared the abilities of all published proposed clinical staging systems to predict time to prostate specific antigen (PSA) failure after radical prostatectomy or external beam radiation therapy for clinically localized prostate carcinoma., Methods: A total of 1441 clinically localized prostate carcinoma patients who were managed with radical prostatectomy at the University of Pennsylvania in Philadelphia (n = 688) or the Brigham and Women's Hospital in Boston (n = 288) or with external beam radiation therapy at the Joint Center for Radiation Therapy in Boston (n = 465) were entered into this study. Patients who received adjuvant or neoadjuvant hormonal or radiation therapy were excluded. Akaike's Information Criterion (AIC) and Schwartz Bayesian Criterion (SBC) estimates, which are comparative measures, were calculated for each clinical staging system. Pairwise comparisons of the AIC and SBC estimates for the most predictive clinical staging systems were performed using a formal bootstrap technique with 2000 replications., Results: Both the staging system based on the risk score and the staging system based on the calculated volume of prostate carcinoma and PSA (cVCa-PSA) optimized the prediction of time to posttreatment PSA failure. The cVCa-PSA system, however, provided a more clinically useful stratification of outcome., Conclusions: Improved clinical staging for patients with localized prostate carcinoma may be possible with parameters obtained during routine evaluation. Validation by other investigators is underway.

Background: In this study, the authors evaluated whether a clinically relevant stratification of prostate specific antigen (PSA) failure free survival (bNED) after definitive local therapy could be made for patients with prostate carcinoma clinically classified as T1 or T2 and pretreatment PSA levels of 4-20 ng/mL., Methods: Multivariate Cox regression analysis and Kaplan-Meier analysis were performed for clinically localized prostate carcinoma patients who presented with PSA levels of 4-20 ng/mL. Three hundred forty-eight of the patients were managed definitively with conventional external beam radiation therapy (median dose, 67 gray), whereas 547 of the patients were managed definitively with a radical retropubic prostatectomy. The outcome tested was time to posttreatment PSA failure. The clinical predictors evaluated included the standard paradigm (PSA, biopsy Gleason score, and clinical stage); type of local therapy; and a newly defined factor, the calculated prostate cancer volume (cV[Ca])., Results: Time to posttreatment PSA failure was equivalent (P = 0.52) independent of the type of local therapy. The cV(Ca) (P < 0.0001), pretreatment PSA (P = 0.003), and clinical classification of T2c (P = 0.04) remained significant predictors of time to posttreatment PSA failure in multivariate analysis., Conclusions: The staging system described herein, which is based on cV(Ca) and PSA, may optimize patient selection for definitive local therapy and entry onto randomized clinical trials examining the use of adjuvant hormonal or chemotherapy in patients with clinically localized disease who present with PSA levels of 4-20 ng/mL. Validation of this staging system by other investigators is currently underway.

Background: Chronic renal failure has been described only rarely in patients treated with the alkylating agent ifosfamide, which is known to cause renal tubular dysfunction and acute renal failure, and the associated histopathologic features have not been well characterized., Methods: This report describes the clinical course and renal histopathologic features in two patients in whom irreversible renal failure occurred requiring permanent dialysis after treatment with ifosfamide., Results: Irreversible renal failure developed in a 60-year-old man with malignant fibrohistiocytoma, requiring chronic dialysis within several months after he received two cycles of ifosfamide in a cumulative dose of 28 g/m2. The second patient, a 53-year-old man with osteogenic sarcoma, received two cycles of ifosfamide with a cumulative dose of 26 g/m2, after initial therapy with cisplatin and doxorubicin. His renal function worsened over the next 11 months, at which time permanent dialysis was initiated. In neither patient were other causes of renal failure apparent. Renal biopsies in both patients showed diffuse tubular epithelial damage with degenerative and regenerative epithelial changes, diffuse interstitial fibrosis, and arterial and arteriolar sclerosis., Conclusions: Irreversible severe renal failure, which appears due to nephrotoxic damage of renal tubular epithelium and/or the renal microvasculature may develop after treatment with ifosfamide. Neither large cumulative doses of ifosfamide nor prior cisplatin treatment are necessary for this toxicity to occur. Because a rising serum creatinine may develop months after completion of treatment with ifosfamide, renal function should be monitored closely both during and after ifosfamide treatment.

Background: The introduction of the endorectal coil magnetic resonance imaging (MRI) technique has improved the accuracy of preoperative staging for prostate cancer. This study quantifies the improvement in the ability to identify clinically unsuspected extraprostatic disease with the use of the endorectal coil MRI., Methods: A retrospective review of the pathologic findings of 347 patients with prostate cancer treated with a radical retropubic prostatectomy was performed. The preoperative clinical indicators including prostate specific antigen (PSA), clinical stage, Gleason score, and endorectal coil MRI data were employed in a multivariate analysis to identify patients who were at high risk for seminal vesicle invasion (SVI) or extracapsular extension (ECE). The sensitivity, specificity, and positive and negative predictive values for predicting SVI and ECE were calculated using the significant clinical indicators found on the multivariate analysis., Results: The clinical factors identified on multivariate analysis as significant predictors of SVI include the endorectal coil MRI data (P < 0.0001), PSA (P = 0.0096), and the Gleason score (P = 0.012). Endorectal coil MRI data (P < 0.0001), PSA (P = .0001), and Gleason score (P < .0001) were significant predictors of ECE. In the patient subgroup with PSA (> 10-20 ng/ml) and Gleason score of 5 to 7, the addition of the endorectal coil MRI data enabled an additional 71 and 27% of patients with SVI and ECE, respectively, to be correctly identified. These patients would have been missed based on the prediction obtained from the PSA and Gleason score alone., Conclusions: The use of the endorectal coil magnetic resonance imaging data, in addition to prostate specific antigen and Gleason score, provides a more accurate prediction of the pathologic outcome of seminal vesicle invasion and extracapsular extension than the PSA and Gleason score alone for the patient subgroup with a PSA of greater than 10 to 20 ng/ml and Gleason score of 5 to 7.

We examined prostatic adenocarcinomas from 19 formalin fixed radical prostatectomy specimens for EGFR by in situ hybridization employing a 24 base synthetic biotin-labeled oligonucleotide probe complementary to the 5' end of EGFR mRNA. All slides were examined by light microscopy using a 25x objective. Each field was given three values: 1) Gleason grade (1-5), 2) Nuclear grade [small (< 5.0 mu), intermediate (5-10 mu), large (> 10 mu)], and 3) EGFR staining intensity score (0, absent; 1, weak; 2+, moderate to strong). A total 851 25x fields of prostatic adenocarcinoma were studied. All cancers demonstrated at least some degree of cytoplasmic EGFR message. The EGFR intensity score correlated best with tumor nuclear size. No correlation with Gleason grade was observed. Cytoplasmic staining was also identified in the basal cell layer of benign glands, high grade prostatic intraepithelial neoplasia, stromal nodules, transitional epithelium, periurethral glands, and ganglion cells. Competitive hybridization experiments using an unlabeled EGFR probe showed markedly diminished hybridization signal, while in situ hybridization with a biotin-labeled EGFR sense probe was negative. Immunohistochemistry on 13 of the tumors with 2 monoclonal antibodies against EGFR showed staining in only 1/13 and 10/13 tumors. EGFR expression appears to be most prominent in tumors of high nuclear grade. Further studies will be necessary to explore this growth factor as a prognostic variable in this tumor.

Three cases of Paget's disease primarily involving the scrotum are reported. One case exhibited positive staining for prostate specific antigen (PSA) and was associated with an underlying, invasive poorly differentiated adenocarcinoma of unknown primary. The other cases were not associated with any underlying or visceral malignancy. The literature on Paget's disease primarily involving the scrotum including clinical presentation, differential diagnosis, treatment, prognosis, and possible histogenetic mechanisms of this disease is discussed.

The in vitro hydroxylation of zoxazolamine was compared with the hydroxylation of benzo[a]pyrene (BP) in full-term placentas from 11 nonsmokers and from 13 women who smoked cigarettes during pregnancy. Cigarette smoking increased the average zoxazolamine and benzo[a]pyrene hydroxylase activities 13- and 39-fold, respectively. A 59-fold range in benzo[a]pyrene hydroxylase activity and a 28-fold range in zoxazolamine hydroxylase activity were found in the placentas of cigarette smokers. A plot of these two enzyme activities showed that zoxazolamine hydroxylase activity was highly correlated, with benzo[a]pyrene hydroxylase activity in the 24 placentas studied (r = 0.98; p less than 0.001). A strong correlation between the above enzymatic activities was also found in 8 placentas which had been stored for 2 yr at -20 degrees C (r = 0.95; p less than 0.001). The results suggest that benzo[a]pyrene and zoxazolamine are metabolized in the human placenta by the same enzyme or by different systems that are under the same regulatory control.