Neuroendocrine differentiation in prostatic carcinoma during hormonal treatment

OBJECTIVES: Neuroendocrine differentiation (NED) is a common feature in adenocarcinoma of the prostate. Several studies suggest that NED may have a major impact on cancer progression as neuroendocrine (NE) secretory products have been shown to possess growth stimulatory effects. NED has also been proposed to constitute part of the mechanism by which a prostate cancer cell progresses toward androgen independence as NE tumor cells have been demonstrated to be devoid of androgen receptor immunoreactivity. In this retrospective study, we evaluated NED status in prostate cancer specimens from patients undergoing androgen ablation therapy. METHODS: The degree of NED in transurethral resection of the prostate (TURP) samples from 53 patients with prostate cancer was investigated by immunocytochemistry using polyclonal rabbit immunoglobin G (IgG) against chromogranin A (CgA). Changes in NED with time were determined by a manual semiquantitative cell counting method. RESULTS: During androgen withdrawal therapy, 21 tumors (40%) displayed increased NED concomitant with histopathologic tumor progression, whereas 29 carcinomas (55%) showed no change in NED status. However, a majority of the histopathologically unchanged tumors displayed marked NED at the first TURP and an increase in NED was by definition not possible. In only 3 cases (5%) was a decrease in NED observed with time. CONCLUSIONS: Androgen ablation therapy may be a contributing factor to the increase in NED of prostatic adenocarcinoma with time, and our findings imply that androgen withdrawal therapy enhances the selection and progression of NED, androgen-independent tumor cells.     

Histologic regression of localized prostatic tumor with neoadjuvant hormonal therapy

OBJECTIVES: To determine the usefulness of preoperative hormone therapy in patients with organ-confined prostatic carcinoma undergoing radical prostatectomy. METHODS: 7 patients with localized prostatic carcinoma are presented. All patients were submitted to radical prostatectomy; 4 had been randomly selected for preoperative hormone therapy. RESULTS: Histological examination showed no nodal involvement in all cases. The tumor could not be identified (Po) in two of the four patients who received hormone therapy. The other two patients were staged down; the Gleason score remained unchanged in one and increased in the other. The patients who did not receive preoperative hormone therapy showed concordant clinical and pathological stages, except one in whom infiltration of the prostatic capsule was observed. No difference was found concerning the facility in performing surgery between the treated and untreated patients. CONCLUSIONS: Hormonal deprivation eliminated the tumor burden in two cases that might have been completely hormone sensitive, with no correlation in the pretreatment histological grade. Clinical downstaging is achieved by this treatment modality. However, further studies in larger series comparing the percentages of downstaging, histological downgrading, absence of tumor cells in the surgical specimen and impact on survivorship are warranted.     

Long-term follow-up of a randomized trial on adjuvant chemotherapy and hormonal therapy in locally advanced breast cancer

Epidemiological research on respiratory syncytial virus (RSV) infections in children was carried out at the Virology Laboratory, University Teaching Hospital (UTH), in Lusaka, Zambia, from January-December 1996. Specimens including 736 nasal washings and 2424 throat swabs were collected from children with acute respiratory infections (ARI) and tested for RSV by enzyme immunoassay and by virus isolation. RSV was isolated in 62 (4.1%) of 1496 throat swabs collected from March to September and was detected in 99 (16.3%) of 609 nasal washings from March to November. The average RSV isolation rate was 2.6% and the average RSV detection rate was 13.5%. The highest RSV isolation (8.1%) and detection (30.5%) rates were in June 1996. RSV antibody in the 278 serum specimens collected from Zambian children, who were hospitalized in the paediatric ward, UTH, was detected using a standard neutralization test. The antibody positive rate was 60-80% in children > 4 years. It is evident that RSV is one of the main causal agents of ARI in children in Zambia.     

The quality of life of prostatic cancer patients

A questionnaire was used to assess the quality of life (QOL) of forty-two outpatients with prostate cancer. Most of the patients were old, so reduced physical comfort was correlated with bodily factors other than those caused by prostate cancer. Many patients with progressive disease reported disease--and treatment--related physical problems that tended to be correlated to the extent of the disease. Many patients treated with female hormones complained of breast induration or discomfort. Patient's sexual life was impaired remarkably. Our treatment for cancer pain would be especially inadequate to cancer pain relief. We must give positive aid to cancer pain relief from now on. Most patients lost sexual interest after developing prostate cancer. Only three of the patients were able to have sexual intercourse. Some of the patients who underwent radical prostatectomy suffered from urinary incontinence after the operation. Thus, the patients' social life was remarkably affected for relative good performance status. Many patients lived only with other elderly individuals. Therefore, it is also important to manage patients in the light of their living environment.     

Adjuvant systemic chemotherapy and hormonal therapy. Effect on local recurrence in the conservatively treated breast cancer patient

BACKGROUND: The purpose of this study is to determine the impact of adjuvant systemic chemotherapy and adjuvant hormonal therapy on local relapse in the conservatively treated breast. MATERIALS AND METHODS: Before December 1989, 548 patients underwent lumpectomy with axillary dissection followed by radiation therapy to the intact breast. Adjuvant systemic therapy was administered as clinically indicated. The majority of patients with pathologically involved lymph nodes received adjuvant systemic therapy, whereas those with pathologically negative lymph nodes received no adjuvant systemic therapy. The majority of patients received a course of radiation therapy either concomitant with or before systemic therapy. In only nine cases was radiation therapy delayed more than 16 weeks after surgery. RESULTS: As of June 1992, the 548 patients had a median follow-up of 6.4 years. In univariate and multivariate Cox regression analysis, patient age and adjuvant systemic chemotherapy were statistically significant independent prognostic factors relating to breast relapse. Those patients who received adjuvant systemic chemotherapy had a lower breast relapse than those who did not. Among patients who received tamoxifen, there was a statistically insignificant trend toward a lower relapse rate compared with those who did not receive tamoxifen. CONCLUSIONS: It appears from this retrospective analysis that patients who received adjuvant systemic therapy, either concomitantly or after their course of radiation therapy, had a lower relapse rate in the conservatively treated breast than those patients who received no adjuvant systemic therapy.     

Molecular staging of prostatic cancer

Despite the improvement current evaluation techniques, approximately 30% of prostatic cancers clinically localized to the gland are understaged. RT-PCR is a sensitive and specific screening method for circulating prostatic cells, proposed as a molecular staging tool. The results obtained with this method and reported in the literature are critically discussed. These results, concerning the detection of circulating PSA- or PSMA-positive prostatic cells, are only indicative, as none of the teams used the same method. No consensus has been reached concerning the equipment used, the choice of oligonucleotide primers, the number of cycles to be applied or even the type of method, classical or "nested". Another possible application of this method is early detection of circulating prostatic cells, possibly neoplastic, during the follow-up of patients treated by radical prostatectomy. Once again, the results of the literature are contradictory. The reliability and reproducibility of molecular biology techniques in routine practice must therefore be demonstrated before these techniques can influence the therapeutic decision concerning prostatic cancer.     

Histological classification of prostatic cancer

Histological classification of prostatic cancer with a special focus on adenocarcinoma was reviewed according to "General Rule for Clinical and Pathological Studies on Prostatic Cancer (The 2nd Edition, 1992) published by Japanese Urological Association and The Japanese Society of Pathology. The points of the classification are as follows; (1) adenocarcinoma is separated into 3 categories, namely, well, moderately and poorly differentiated types, by structural features. (2) nuclear grading does not commit for making a subclassification of prostatic adenocarcinoma. The other types of primary malignancies are rare in the prostate. Prostatic intraepithelial neoplasia should be discussed in the further revision of the classification.     

Viral oncology of prostatic cancer

1. A method is described for the measurement of liver blood flow without hepatic venous catheterization by the injection of the a single dose of bromosulphthalein and the analysis of the graph of the plasma disappearance of the indicator. 2. The rationale of the method was tested in three systems which covered a wide range of flow rates. The first system was a physical model with a haemodialyser in which the calculated flow could be compared with the flow measured directly. The second was in anesthetized dogs, in which the calculated flow was compared with that measured by continuous infusion and hepatic venous catheterization, based on the Fick principle. The third system was in unanaesthetized turkeys, in which metabolism of bromosulphthalein does not occur. The calculated flow was compared with the flow measured simultaneously by the uptake of collodial particles by the Kupffer cells. 3. In all three systems the correspondence between the two methods of measuring liver blood flow was good, the differences between them being not statistically significant. 4. The method has been applied to measurements of liver blood flow in man and animals and gives results comparable with those reported by other workers.     

The role of chemotherapy in head and neck cancer

We studied the effect of cytoreductive chemotherapy in head and neck cancer and analyzed it in terms of efficacy, remission rates, and duration, as well effect on survival. Single-agent chemotherapy, which formerly was used as a palliative therapy in recurrent and metastatic disease, had little affect on survival. More recently, multi-agent chemotherapy trials have shown significantly higher response rates, but this success has not translated into an added survival benefit. These findings led to the introduction of multi-agent chemotherapy into the induction (neoadjuvant) clinical setting. In these clinical circumstances, better objective response rates were found, particularly in the previously untreated patient. Although this therapy has resulted in better control of local disease, the impact on survival is not yet clear. Adjuvant chemotherapy is most useful in patients who have a high risk of relapse. Therapy appears to decrease its incidence, particularly at distant sites. Finally, chemoradiation trials have shown that this treatment provides a survival advantage, but at the cost of a significant increase in toxicity.     

Apoptosis and cancer chemotherapy

Cytotoxic drugs currently remain as the basis for the chemotherapy of metastatic cancer. Why they fail to kill sufficient tumour cells in the major human solid cancers, such as the carcinomas, is suggested in this review to be due to the inherent inability of these cells to engage apoptosis after drug-induced damage. As a paradigm for drug resistant cancers, the resistance of bladder carcinoma cell lines to DNA damaging drugs is described here in terms of their response to the topoisomerase II poison etoposide. 60%-70% of bladder carcinomas have mutant p53; this can prevent the detection of and response to DNA damage. In vitro studies with a bladder carcinoma cell line containing a wild type p53 showed that it underwent a G1 checkpoint after etoposide, potentially allowing DNA damage repair, as well as apoptosis. In lines with mutant or non-functional p53 there is no checkpoint and no apoptosis. All lines showed constitutive expression of bcl-2 and bcl-XL (the suppressors of apoptosis) with low and non-inducible levels of bax (a promoter of apoptosis). Taken together, this menu of gene expression is more favourable to survival than apoptosis after the imposition of drug-induced DNA damage and may contribute to their inherent drug resistance.     

Pharmacogenetics and cancer chemotherapy

Cancer chemotherapy is limited by significant inter-individual variations in responses and toxicities. Such variations are often due to genetic alterations in drug metabolising enzymes (pharmacokinetic polymorphisms) or receptor expression (pharmacodynamic polymorphisms). Pharmacogenetic screening prior to anticancer drug administration may lead to identification of specific populations predisposed to drug toxicity or poor drug responses. The role of polymorphisms in specific enzymes, such as thiopurine S-methyltransferases (TPMT), dihydropyrimidine dehydrogenase (DPD), aldehyde dehydrogenases (ALDH), glutathione S-transferases (GST), uridine diphosphate glucuronosyl-transferases (UGTs) and cytochrome P450 (CYP 450) enzymes in cancer therapy are discussed in this review.     

The use of chemotherapy resistance in cancer treatment

It is not inconceivable that everything except the basic structure of an office building could be prefabricated in the near future. Quality and schedule are nearly always improved with prefabrication due to the simple change from an uncontrolled work environment to a controlled one. One Ludgate Place, is a 23,600 m2, ￡30,000,000 speculative commercial development in central London. This high quality office building has an exposed structural steel frame, within which are fitted prefabricated cladding panels. This paper combines the results from two research programs. The first in the area of prefabrication and the second in the management of high quality cladding construction. The writers describe the Ludgate Place project, incorporating the cladding design, testing, assembly, and installation. Factors that influenced the decision to use prefabrication are presented and evaluated, namely, cost; time; quality; past experience; design; weather joints; performance tests; site logistics; and safety. Construction interfaces and tolerances, particularly between cladding and structure, are discussed, and the future of prefabricated cladding is considered.     

Contemporary hormonal management of advanced prostate cancer

The traditional definition of "advanced" prostate cancer includes only patients with widespread osteoblastic or soft-tissue metastases (clinical or pathologic stage T any N any M1; or stage D2). Current evidence indicates that this definition should be broadened. Because many patients with T3 disease or local lymph node metastases progress to distant metastases, the concept of advanced prostate cancer should also include stages C and D1 (T3, T4, and any T N1). Furthermore, based on pretreatment prostate-specific antigen (PSA) levels, many men treated for clinically localized disease will progress rapidly and, depending on their age and general health, should be included in the advanced-disease category. Also, using prognostic marker modeling with PSA, tumor grade, and other factors, recurrences can be predicted even earlier in many cases. This may be particularly significant in light of recent clinical data indicating that early androgen ablation therapy delays disease progression and improves survival in patients with advanced (M0 or M1) disease. The luteinizing hormone-releasing hormone (LHRH) agonists have become the preferred method of androgen ablation in patients with advanced prostate cancer. Use of an LHRH agonist, alone or combined with an antiandrogen, is more acceptable to many patients than orchiectomy and lacks the potential cardiotoxicity associated with estrogens. Combined hormonal therapy remains controversial but may provide a modest survival benefit, especially in men with minimal metastatic disease. Intermittent hormonal therapy has great appeal, particularly because of the potentially deleterious effects of long-term hormonal therapy; however, its efficacy has yet to be proven.     

Radical prostatectomy for localized prostatic cancer

Curatively intended surgical management of clinically localized prostate cancer has recently been introduced in Denmark. This literature review covers results of preoperative evaluation, impact of stage and grade on outcome, and the results following radical prostatectomy.     

Application and limitation of neoadjuvant hormonal therapy for prostate cancer

Of 156 patients, 111 (clinical stage T1a-b; 21, T1c; 17, T2a-b; 36, T2c; 27, T3; 10) immediately underwent radical prostatectomy (surgery group), and 45 (clinical stage T1a-b; 8, T1c; 4, T2a-b; 10, T2c; 9, T3; 14) received neoadjuvant hormonal therapy (NHT group). NHT offered probability of increasing organ-confined cancer(OCC; pathological stage pT2 or lower N0M0) in the following group, which contains (a) patients who had moderately differentiated adenocarcinoma in the biopsy specimen and T2b or lower diseases, and (b) those who had well differentiated adenocarcinoma, T2c diseases and PSA levels of 10 ng/ml or higher, referred to as "OCC suitable criteria". Of 156 patients, 51 (33%) met OCC suitable criteria. In those cases, the proportion of OCC in NHT group was significantly higher than that in surgery group (11/12 (92%) vs. 16/39 (41%), p = 0.002). NHT is useful for increasing OCC in patients who meet OCC suitable criteria.     

Quality assurance in radiotherapy of prostatic cancer

External beam radiotherapy is a widely experimented treatment modality in prostatic cancer. Recently published studies have documented a close dependence of clinical results, in terms of local control and toxicity in particular, on radiation therapy quality. Efforts to improve results of conventional radiotherapy were directed towards the identification of new therapeutic modalities (conformal therapy, fast neutron radiotherapy, neoadjuvant hormonotherapy) as well as towards the optimization of treatment accuracy. In this respect, the following procedures have been particularly effective: 1. the systematic use of CT and retrograde urethrography in PTV definition; 2. immobilization systems which allow a significant reduction in positioning errors; 3. checks before and during treatment by "portal imaging" which allow the identification and correction of a relevant percentage of inaccuracies. The general evolution in treatment planning occurred in recent years has introduced into prostatic cancer radiotherapy new methods and calculation algorithms. While at present the use of new and at the same time complex techniques makes the need for quality assurance of radiation treatments increasingly critical, it is in any case a daily requirement even in most conventional routine treatments.     

The effect of intraperitoneal and intra-aortic chemotherapy for unresectable gastric cancer

Regional chemotherapy was given 16 unresectable gastric cancer patients. Two types of the chemotherapy, intraperitoneal (IP) and intraaortic (IA) administration, were carried out. The control group was comprised of 17 patients. The response of the chemotherapy for primary tumor was 36.4% in the IP group and 20% in the IA one. Among these patients, 2 of 11 in IP and 1 of 5 in IA were able to resect the primary tumor. The 50% survival time of IP, IA and control was 347, 227 and 78 days, respectively. One-year survival rates of IP, IA and control were 68%, 29% and 0%, respectively. IP showed a significantly longer survival rate than controls (p < 0.001). All but one patient was able to stay at home. Intraperitoneal chemotherapy showed both local and systemic effects in unresectable gastric cancer.