Quality of life after radical trachelectomy for early-stage cervical cancer: A 5-year prospective evaluation.

OBJECTIVES: To longitudinally assess quality of life (QOL) in women undergoing radical trachelectomy for early-stage cervical cancer. METHODS: We prospectively enrolled patients with stage IA1-IB1 cervical cancer prior to undergoing radical trachelectomy to complete validated QOL instruments. These instruments included the General Health-Related QOL (SF-12), Functional Assessment of Cancer Therapy-Cervix (FACT-Cx), MD Anderson Symptom Inventory (MDASI), Female Sexual Functioning Index (FSFI), and Satisfaction with Decision scale (SWD). Instruments were filled out at baseline, postoperatively at 6weeks, 6months, 1year, and annually thereafter for 4years. RESULTS: Thirty-nine patients enrolled in the study, and 32 patients were evaluable. The scores for FSFI-arousal (p=0.0002), lubrication (p<0.0001), orgasm (p=0.006), pain (p=0.01), satisfaction (p=0.03) and total score (p=0.004) showed a significant decline at 6weeks then returned to baseline levels by 6 months. The scores for FACT-Cx functional well-being (p=0.02) and physical well-being (p<0.0001), SF-12 bodily pain (p<0.0001), physical functioning (p<0.0001), role physical (p<0.0001), role emotional (p=0.03), social functioning (p=0.002), and MDASI total (p=0.04) showed significantly worsened symptoms at 6weeks then returned to baseline by 6months. The scores for FACT-Cx emotional well-being showed significant worsening of symptoms that persisted at 6-weeks (p=0.004), 6months (p=0.007), 1year (p=0.001), 2years (p=0.002), and 4 years (p=0.03). There was no difference in SWD. CONCLUSIONS: Several quality of life assessments decline immediately postoperatively after radical trachelectomy, however, return to baseline thereafter. The long-term emotional impact of this surgery highlights a need for perioperative counseling in these patients.

Body composition and survival in the early clinical trials setting.

PURPOSE: Delineate the relationships between body composition parameters, 90-day mortality and overall survival, and correlate them with known prognostic factors in an early clinical trials clinic. PATIENTS AND METHODS: We studied 306 consecutive patients with various tumours; body composition was analysed by computerised tomography images. Survival was measured from the first clinic visit, at 90-day period and until death/last follow-up visit. RESULTS: Median patient age was 56 years; 159 patients were men. Ninety-day mortality rate was 12%. Median overall survival was 9 months. In multivariate analyses, high MD Anderson Cancer Center (MDACC) score (p < 0.0001) [lactate dehydrogenase (LDH) > normal, albumin < normal, Eastern Cooperative Oncology Group (ECOG) performance status > 1, metastatic sites > 2, gastrointestinal (GI) tumours], low skeletal muscle index (SMI) (p = 0.0406) and male gender (p = 0.0077) were independent predictors of poor survival. If Royal Marsden Hospital (RMH) score (LDH > normal, albumin 2) was used in lieu of MDACC score, it was also significant (p = 0.0003). Including SMI and gender in the MDACC or RMH score improved the accuracy of the original model (p = 0.006 and p = 0.0037, respectively). CONCLUSION: Patients with low SMI have shorter survival. Gender and SMI strengthens the accuracy of MDACC or RMH scores as prognostic tools. Prospective validation of these findings is warranted.

Genotypic and allelic frequencies of SULT1A1 polymorphisms in women receiving adjuvant tamoxifen therapy.

Human sulfotransferase 1A1 (SULT1A1) is involved in the metabolism of a number of substances including 4-hydroxytamoxifen. It has been shown that patients who are homozygous for the variant SULT1A1 *2/*2 have lower catalytic activity. Previous data has suggested that patients with this particular genotype may be at a greater risk of developing breast cancer or not responding to tamoxifen therapy. To date, there is no data within the Hispanic population on the genotypic and allelic frequencies of the SULT1A1 gene. Two hundred and ninety-six patients were genotyped by either restriction fragment length polymorphism (RFLP) or Pyrosequencing for the SULT1A1 exon 7 polymorphism. The genotypic frequency was 0.47 (*1/*1), 0.40 (*1/*2) and 0.13 (*2/*2) in Caucasians and 0.37 (*1/*1), 0.45 (*1/*2) and 0.18 (*2/*2) in Hispanics. Although Hispanics have a higher genotypic frequency of variant genotypes this difference was not statistically significant (p=0.26). SULT1A1 genotype did not correlate with any prognostic or predictive markers associated with breast cancer. Future evaluations will assess the functional significance of this polymorphism on survival.

Production of human type I collagen in yeast reveals unexpected new insights into the molecular assembly of collagen trimers.

Substantial evidence supports the role of the procollagen C-propeptide in the initial association of procollagen polypeptides and for triple helix formation. To evaluate the role of the propeptide domains on triple helix formation, human recombinant type I procollagen, pN-collagen (procollagen without the C-propeptides), pC-collagen (procollagen without the N-propeptides), and collagen (minus both propeptide domains) heterotrimers were expressed in Saccharomyces cerevisiae. Deletion of the N- or C-propeptide, or both propeptide domains, from both proalpha-chains resulted in correctly aligned triple helical type I collagen. Protease digestion assays demonstrated folding of the triple helix in the absence of the N- and C-propeptides from both proalpha-chains. This result suggests that sequences required for folding of the triple helix are located in the helical/telopeptide domains of the collagen molecule. Using a strain that does not contain prolyl hydroxylase, the same folding mechanism was shown to be operative in the absence of prolyl hydroxylase. Normal collagen fibrils were generated showing the characteristic banding pattern using this recombinant collagen. This system offers new opportunities for the study of collagen expression and maturation.

Comparison of the structural motifs of acetoacetanilides and related azo pigments

The structures of three methyl-substituted acetoacetanilides and of an azo pigment derived from one of them are presented and discussed together with a review of related known crystal structures. By considering the position of any aromatic substituents it is possible to predict whether the simple acetoacetanilides adopt planar structures with intramolecular hydrogen bonding or twisted structures featuring intermolecular hydrogen bonding. However, we find that the same crystal engineering rules cannot be applied to the related azo pigments: this is apparently due to the presence of an sp(2) atom which facilitates the adoption of planar conformations. The thermal properties of the acetoacetanilides were measured by DSC and are discussed with reference to their crystal structures.

Complete non-puerperial uterine inversion as a result of a uterine sarcoma.

Complete non-puerperial uterine inversion is rare and when present is usually associated with a prolapsed submucous fibroid. The inversion in this case was associated with a uterine sarcoma in an 88 year old diabetic patient, gravida 13, who presented with a four month history of intermittent vaginal bleeding. She was successfully managed with a total abdominal hysterectomy and some of the difficulties with diagnosis and management are highlighted.

Complete non-puerperial uterine inversion as a result of a uterine sarcoma

Complete non-puerperial uterine inversion is rare and when present is usually associated with a prolapsed submucous fibroid. The inversion in this case was associated with a uterine sarcoma in an 88 year old diabetic patient, gravida 13, who presented with a four month history of intermittent vaginal bleeding. She was successfully managed with a total abdominal hysterectomy and some of the difficulties with diagnosis and management are highlighted.

Complete non-puerperial uterine inversion as a result of a uterine sarcoma

Complete non-puerperial uterine inversion is rare and when present is usually associated with a prolapsed submucous fibroid. The inversion in this case was associated with a uterine sarcoma in an 88 year old diabetic patient, gravida 13, who presented with a four month history of intermittent vaginal bleeding. She was successfully managed with a total abdominal hysterectomy and some of the difficulties with diagnosis and management are highlighted.(Au)

Production of recombinant human type I procollagen trimers using a four-gene expression system in the yeast Saccharomyces cerevisiae.

The expression of stable recombinant human collagen requires an expression system capable of post-translational modifications and assembly of the procollagen polypeptides. Two genes were expressed in the yeast Saccharomyces cerevisiae to produce both propeptide chains that constitute human type I procollagen. Two additional genes were expressed coding for the subunits of prolyl hydroxylase, an enzyme that post-translationally modifies procollagen and that confers heat (thermal) stability to the triple helical conformation of the collagen molecule. Type I procollagen was produced as a stable heterotrimeric helix similar to type I procollagen produced in tissue culture. A key requirement for glutamate was identified as a medium supplement to obtain high expression levels of type I procollagen as heat-stable heterotrimers in Saccharomyces. Expression of these four genes was sufficient for correct assembly and processing of type I procollagen in a eucaryotic system that does not produce collagen.

The First Red Azo Lake Pigment whose Structure is Characterized by Single Crystal Diffraction.

A model for red azo pigment Ca4B was characterized structurally using synchrotron radiation. This highly anisotropic ladder structure represents a new structural class in azo pigment chemistry. The picture shows that the calcium atoms coordinate in a complex manner to three azo ligands (one terdentate, one bidentate, and one monodentate) and two water molecules simultaneously.

Differential effect of finasteride on the tissue androgen concentrations in benign prostatic hyperplasia.

OBJECTIVE: The 5 alpha-reductase inhibitor, finasteride, provides a logical medical treatment for benign prostatic hyperplasia (BPH). However, the effects of chronic finasteride treatment on prostatic androgen levels, 5 alpha-reductase activity and tissue prostatic specific antigen (PSA) have not been studied. We have examined prostate tissue androgen concentrations and 5 alpha-reductase activity of the gland in men with BPH treated with the drug for 3 months. DESIGN AND PATIENTS: Twenty-eight patients with clinically diagnosed BPH, awaiting transurethral resection of the prostate, were entered in a double-blind placebo controlled study. Nineteen patients were randomly allocated to treatment with finasteride (5 mg daily) and 9 received placebo for 3 months. MEASUREMENTS: Prostate specimens were collected immediately following surgery and analysed for testosterone, dihydrotestosterone (DHT), androstenedione, 5 alpha-reductase activity and PSA. Blood specimens obtained before the start and immediately following treatment were also tested for steroid hormone concentrations and PSA levels. RESULTS: There was no significant difference in the median levels of intraprostatic testosterone (P = 0.77), DHT (P = 0.46) and androstenedione (P = 0.09) between the finasteride and placebo groups. However, the 5 alpha-reductase activity of the placebo group (237.9 pmol DHT/g tissue/30 min) was approximately 10 times that of the finasteride group (21.5 pmol DHT/g tissue/30 min; P = 0.0008). Although we were unable to detect any differences in the PSA concentrations of the prostate glands, there was a significant difference (P = 0.0002) in the median percentage change of serum PSA concentrations for the two patient groups. Serum DHT levels were also depleted (P = 0.038) whilst serum testosterone was increased (P = 0.054) in the finasteride patients when compared to the placebo group. Furthermore our study demonstrated no correlation between the in vitro 5 alpha-reductase activity of the gland and tissue DHT concentrations. CONCLUSIONS: Whilst finasteride treatment induced a reduction in serum dihydrotestosterone and prostatic specific antigen levels with a concomittant increase in blood testosterone concentrations, the impact of the drug on tissue androgen concentrations varied considerably from one patient to another. The differential effect of the drug on tissue androgen concentrations suggests that in the human prostate there are possibly more than one isoform of 5 alpha-reductase responsible for the accumulation of DHT in the gland.

Comparison of phytotherapy (Permixon) with finasteride in the treatment of benign prostate hyperplasia: a randomized international study of 1,098 patients.

BACKGROUND: Controversy regarding the relative efficacy of treatments for the relief of the symptoms of benign prostatic hyperplasia (BPH). METHODS: This was a 6-month double-blind randomized equivalence study that compared the effects of a plant extract (320 mg Permixon) with those of a 5 alpha-reductase inhibitor (5 mg finasteride) in 1,098 men with moderate BPH using the International Prostate Symptom Score (IPSS) as the primary end-point. RESULTS: Both Permixon and finasteride decreased the IPSS (-37% and -39%, respectively), improved quality of life (by 38 and 41%), and increased peak urinary flow rate (+25% and +30%, P = 0.035), with no statistical difference in the percent of responders with a 3 ml/sec improvement. Finasteride markedly decreased prostate volume (-18%) and serum PSA levels (-41%); Permixon improved symptoms with little effect on volume (-6%) and no change in PSA levels. Permixon fared better than finasteride in a sexual function questionnaire and gave rise to less complaints of decreased libido and impotence. CONCLUSIONS: Both treatments relieve the symptoms of BPH in about two-thirds of patients but, unlike finasteride, Permixon has little effect on so-called androgen-dependent parameters. This suggests that other pathways might also be involved in the symptomatology of BPH.

Testosterone metabolism in primary cultures of epithelial cells and stroma from benign prostatic hyperplasia.

We studied the metabolism of testosterone in primary cultures of prostate epithelial cells and fibroblasts obtained from patients with benign prostatic hyperplasia (BPH). The conversion of 3H-testosterone in both cell cultures was predominantly to the oxidative pathway, with the formation of 3H-androstenedione increasing with cell number and time of incubation. Although we also detected some 5 alpha-reductase activity in these cells, the activity in the stroma component (0.00688 pmol/mg protein/min) was nonetheless insignificant when compared to the 5 alpha-reductase activity in the tissue of origin (0.0616 pmol/mg protein/min) and well below the 17 beta-hydroxysteroid dehydrogenase activity of the same cells (0.0518 pmol/mg protein/min). The aromatase activity in our cells was also measured by two separate techniques, but neither the deuterium procedure nor the production of oestrone from androgen precursors yielded any positive results, suggesting that under these experimental conditions there was no aromatase activity within the cells. The shift from the reductive to the oxidative pathways in these primary cell cultures was reminiscent of the androgen-metabolizing enzyme profiles seen in poorly differentiated prostate cancer. Whether this transition is an obligatory step in the development of hormone refractiveness remains to be elucidated.

Cytokine modulation of epidermal growth factor receptor expression on bladder cancer cells is not a major contributor to the antitumour activity of cytokines.

Epidermal growth factor is a potential mitogen for many different human tumours. Its effect is mediated via a bispecific receptor (EGFR), the expression of which correlates well with invasive disease. We investigated the modulation of EGFR by cytokines produced following bacillus Calmette Guerin (BCG)-immunotherapy. Our data demonstrate the IFN gamma, TNF alpha and IL-1 alpha can decrease the expression of EGFR on some bladder tumour cell lines. IFN gamma reduced EGFR expression on two of eight cell lines (RT4, SD). However, IL-1 and TNF did not share this activity. When cells were treated with a combination of all three cytokines, EGFR was decreased on three cell lines (RT4, RT112, SD) and furthermore, the change in the receptor expression was even more marked. Treatment with phorbol ester (thereby activating protein kinase C) resulted in rapid disappearance of the receptor from the cell surface. Interestingly, the decrease of EGFR expression did not require protein synthesis. Although the cytokines studied could down modulate EGFR, this only occurred on three out of eight cell lines; therefore, it is unlikely that the suppression of proliferative activity caused by cytokine-induced decrease of EGFR expression is central to the antitumour action of BCG therapy, but in a proportion of tumours this mechanism may be involved.

Interleukin-6 production by bladder tumors is upregulated by BCG immunotherapy.

PURPOSE: To determine whether BCG therapy could upregulate interleukin-6 (IL-6) production in human transitional cell carcinomas (TCC). MATERIALS AND METHODS: Immunohistochemistry of tumor biopsies and urinary cytospins and ELISA studies of urine from bladder cancer patients and TCC cell-line supernatants, before and after exposure to BCG, were performed. RESULTS: Constitutive staining for IL-6 was found in the majority of bladder tumors. Interleukin-6 was detected in the urine of all 13 patients with carcinoma in situ and increased 5-fold during BCG therapy. Levels were variable but were greater in nonresponders (p < 0.01). During therapy both detached bladder urothelial cells and polymorphonuclear leukocytes stained for IL-6. Production of IL-6 increased in only 3 cell lines after exposure to BCG, but all 7 cell lines showed increases after exposure to interferon-gamma (p = 0.015). Grade 3 cell lines showed much greater upregulation than grade 1 and 2 cell lines. CONCLUSIONS: The increase in IL-6 during BCG therapy may be caused by urothelial cells as well as leukocytes. The higher levels seen in nonresponders may be due to either higher grade or persisting tumor.

A case for synchronous reduction of testicular androgen, adrenal androgen and prolactin for the treatment of advanced carcinoma of the prostate.

The present study was undertaken mainly to investigate whether prolactin manipulation combined with maximal androgen blockage improves the effectiveness of treatment in advanced prostatic cancer. The efficacy of oral hydrocortisone as an alternative to commercial anti-androgens in reducing the adrenal androgens, and of bromocriptine in reducing the prolactin level were also examined. A consecutive series of 30 patients with untreated and advanced prostatic cancer were entered into a three-arm prospective randomised trial. 10 patients received subcapsular orchiectomy alone (arm 1), another 10 had subcapsular orchiectomy plus flutamide (arm 2), and the remaining 10 had subcapsular orchiectomy plus oral hydrocortisone and bromocriptine (arm 3). Clinical and biochemical parameters, including trans-rectal ultrasound-determined prostatic volumes, hormonal profiles and radionuclide bone scan were evaluated at regular intervals. At 12 months, serum testosterone was reduced by more than 90% in all arms, however, maximum suppression of androstenedione, prolactin, and reduction of prostatic volumes were only observed in arm 3; this was reflected by the significant improvement in clinical response in arm 3 compared with other arms. This study suggests that a combined maximal suppression of androgens and prolactin offers a significant improvement in response over conventional treatments without prolactin suppression in the treatment of advanced prostatic cancer. Importantly, a better clinical outcome in arm 3 was still apparent at the end of 36 months.

Shared care between general practitioners and urologists in the management of benign prostatic hyperplasia: a survey of attitudes among clinicians.

Recent community-based population surveys have revealed a much greater prevalence of benign prostatic hyperplasia than previously suspected. From these data it has been projected that there may be more than 2 million men in the UK whose quality of life is to some extent impaired by this disorder. Since there are only 330 fully trained urologists in this country it will not be feasible for every individual presenting with prostatism to be assessed by a specialist. In an attempt to provide a more rational basis from which family practitioners can decide whether or not to refer a patient for a specialist opinion a 'shared care' flow diagram was developed and assumptions contained within field tested by means of a postal questionnaire which was sent to 2020 urologists, family practitioners and other interested clinicians. There was general agreement with most of the precepts set out in the flow diagram, the main exception was a rejection of the suggestion that every patient with prostatism should have a prostate-specific antigen level determined before referral. We conclude that there seems a consensus among respondents that a shared care approach to the management of BPH may both improve the standard of care provided in this area by family practitioners and allow hard pressed urologists to focus greater attention on those patients whose conditions require surgical expertise to resolve.