Prevalence of hot flushes during and after neoadjuvant hormonal therapy for localized prostate cancer

OBJECTIVES: We sought to determine the prevalence of hot flushes after neoadjuvant hormonal therapy. METHODS: Forty-three patients who received neoadjuvant hormonal therapy before radical prostatectomy were asked to complete a questionnaire regarding hot flushes. RESULTS: Complete information was available for 35 of the 43 patients. No hot flushes were noted in 20%; in 69%, hot flushes were noted during treatment but resolved after termination of treatment; and in 11%, hot flushes continued for at least 3 months after cessation of hormonal therapy. Analyzing the data with respect to duration of hormonal therapy showed that patients receiving neoadjuvant hormonal therapy for more than 4 months had the highest incidence of persistent hot flushes. CONCLUSIONS: Hot flushes will be noted in 80% of patients who receive neoadjuvant hormonal therapy. In approximately 10%, hot flushes will continue for a significant period after hormonal therapy is terminated. Patients should be apprised of this potential side effect.     

Histologic regression of breast cancer after primary (neoadjuvant) chemotherapy

Primary (neoadjuvant) chemotherapy of locally advanced breast carcinomas is performed to locally reduce the tumour mass and to improve the operability. Recently, the indication for primary chemotherapy has been extended for preoperative treatment in breast conserving surgery. In an ongoing clinical trial we examined the resection specimens of 51 mammary carcinomas after primary chemotherapy. These patients had received a neoadjuvant therapy with epirubicin/cyclophosphamide for size reduction of large (> 3 cm) but operable tumours (pretreatment median tumour size 4.5 cm by mammography). The tumour response was evaluated pathologically and compared with the clinical tumour regression that was observed in over two-thirds of all cases. We classified the regressive changes using a semiquantitative scoring system from 0 to 4 (0 = no effect, 1 = resorption and tumour sclerosis, 2 = minimal residual invasive tumour [< 0.5 cm], 3 = residual noninvasive tumour only, 4 = no tumour detectable). The aim of this study was to evaluate the improvement of operability objectively and to correlate the histology of the primary tumour with the response to treatment. With invasive lobular carcinomas, the tumour size after therapy was reduced less than average and irrespective of the amount of histological tumour cell reduction, largely due to the stromal content of these neoplasms. Invasive ductal carcinomas with extensive or predominant intraductal component also underwent only a slight decrease in tumour size; this was because of the lack of tumour response with the intraductal component. Well differentiated tubular carcinomas were particularly resistant to primary chemotherapy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Radiation therapy with neoadjuvant hormonal therapy for prostate cancer confined to pelvis

Neoadjuvant endocrine treatment prior to radical prostatectomy for prostate cancer confined to pelvis has of some value to prevent progression although there are many controversies. In order to improve the prognosis of locally advanced prostate cancer (stage B2 and C), definitive radiotherapy with neoadjuvant endocrine therapy has been investigated. Endocrine therapy reduces the volume of prostate, thus reduces the amount of side effect via reducing the area of irradiated normal tissue. Effect of radiation and that of endocrine therapy to induce apoptosis might be synergistic. The result is favorable although the follow-up period is too short. Further studies are needed to make conclusion.     

Treatment of clinically localized prostatic cancer--endocrine therapy

We assessed the actuarial survival of 28 patients with localized prostate cancer who were treated with endocrine therapy in comparison with that of 19 patients who had radical prostatectomy between 1972 and 1995. There were no significant differences among the cause-specific curves and clinical disease-free survival of patients treated with endocrine therapy and radical prostatectomy but the all-cause survival curves favored the surgery group. The results of endocrine therapy alone were unsatisfactory for the patients with high grade tumors. In conclusion, the patients with localized prostate cancer at high risk of death from other complications are reasonable candidates for endocrine therapy.     

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.     

Current studies of combined radiotherapy-hormone therapy in localized and locally advanced prostatic cancers

In locally advanced prostate cancer three clinical randomized trials have shown that external irradiation combined with LHRH analogue with or without antiandrogen improved survival: disease-free survival, local recurrence-free survival, metastasis-free survival (P < 0.001). EORTC trial 22863 alone has shown a significant improvement of overall survival (P = 0.001), with an LHRH analogue (goserilin acetate, zoladex) started the first day of irradiation and followed every 4 weeks for 3 years; for RTOG trial 85-31 the same LHRH analogue started during the last week of irradiation and given until relapse increases survival of patients with poor differentiated tumours with gleason score ranging from 8 to 10 (P = 0.03). In locally confined prostate carcinoma randomized trials are ongoing to assess the impact of conventional irradiation or three dimensional conformal radiotherapy with or without adjuvant hormonotherapy.     

Predictors of improved outcome for patients with localized prostate cancer treated with neoadjuvant androgen ablation therapy and three-dimensional conformal radiotherapy

PURPOSE: To identify prognostic variables that predict for improved biochemical and local control outcome in patients with localized prostatic cancer treated with neoadjuvant androgen deprivation (NAAD) and three-dimensional conformal radiotherapy (3D-CRT). MATERIALS AND METHODS: Between 1989 and 1995, 213 patients with localized prostate cancer were treated with a 3-month course of NAAD that consisted of leuprolide acetate and flutamide before 3D-CRT. The purpose of NAAD in these patients was to reduce the preradiotherapy target volume so as to decrease the dose delivered to adjacent normal tissues and thereby minimize the risk of morbidity from high-dose radiotherapy. The median pretreatment prostate-specific antigen (PSA) level was 15.3 ng/mL (range, 1 to 560 ng/mL). The median 3D-CRT dose was 75.6 Gy (range, 64.8 to 81 Gy), and the median follow-up time was 3 years (range, 1 to 7 years). RESULTS: The significant predictors for improved outcome as identified in a multivariate analysis included pretreatment PSA level < or = 10.0 ng/mL(P < .00), NAAD-induced preradiotherapy PSA nadir < or = 0.5 ng/mL (P < .001), and clinical stage < or = T2c (P < .04). The 5-year PSA relapse-free survival rates were 93%, 60%, and 40% for patients with pretreatment PSA levels < or = 10 ng/mL, 10 to 20 ng/mL, and greater than 20 ng/mL, respectively (P < .001). Patients with preradiotherapy nadir levels < or = 0.5 ng/mL after 3 months of NAAD experienced a 5-year PSA relapse-free survival rate of 74%, as compared with 40% for patients with higher nadir levels (P < .001). The incidence of a positive biopsy among 34 patients pretreated with androgen ablation was 12%, as compared with 39% for 117 patients treated with 3D-CRT alone who underwent a biopsy (P < .001). CONCLUSION: For patients treated with NAAD and high-dose 3D-CRT, pretreatment PSA, preradiotherapy PSA nadir response, and clinical stage are important predictors of biochemical outcome. Patients with NAAD-induced PSA nadir levels greater than 0.5 ng/mL before radiotherapy are more likely to develop biochemical failure and may benefit from more aggressive therapies.     

The hormonal and chemotherapy of prostatic cancer

Adenocarcinoma of the prostate is one of the most common malignant tumors in adult males. Hormonal therapy is the treatment of choice for patients with systemic disease concerning 80% response rate. Androgen ablation is now the first hormonal manipulation and can be achieved either by means of bilateral orchiectomy or of LH-HR agonist therapy: both are equally effective. Total androgen blockage (association between orchiectomy or LH-RH agonist and non-steroidal anti-androgens) would be reserved for controlled clinical trials only. Estrogens had the same efficacy, but revealed the serious cardio-vascular events. Endocrine therapy does not prolong survival but provides good palliation. Palliation should be given when there is something to palliate. Prostate cancer is usually not recognized as being sensitive to cytotoxic agents. Single agent or combination chemotherapy has not been shown to have a role as first line treatment of disseminated disease and is usually used for hormone refractory disseminated disease.     

Complete regression of established human glioblastoma tumor xenograft by interleukin-4 toxin therapy

No curative therapy is available for malignant gliomas. We have discovered that human glioblastoma cells express high affinity interleukin-4 receptor (IL-4R), which is an attractive target for receptor-directed IL-4 toxin therapy. The IL-4 toxin, IL-4(38-37)-PE38KDEL, is a fusion protein containing translocation and enzymatic domains of Pseudomonas exotoxin and a circularly permuted human IL-4. The IL-4 toxin binds specifically to the IL-4R and is highly cytotoxic to glioblastoma cells, as determined by clonogenic and protein synthesis inhibition assays. Intratumoral administration of the IL-4 toxin given on alternate days for 3-4 doses into U251 glioblastoma flank tumors in nude mice, showed a complete remission of small (approximately 13 mm3) and large (approximately 60 mm3) tumors in all animals, without any evidence of toxicity. A significant antitumor activity was also observed when the IL-4 toxin was administered via i.p. and i.v. routes. These results demonstrate that the IL-4 toxin may be a new therapeutic drug for the treatment of human glioblastoma. Therefore, we have begun a Phase I clinical trial with IL-4(38-37)-PE38KDEL for treatment of human glioblastoma.     

Spontaneous regression of localized neuroblastoma detected by mass screening

PURPOSE: A retroperitoneal access is commonly used for open urological procedures. Since the introduction of the balloon dissecting technique by Gaur this anatomical route has also been used for laparoscopic surgery. We present our experience with retroperitoneoscopy in 200 cases. MATERIALS AND METHODS: From December 1992 to October 1997 a total of 200 retroperitoneoscopic procedures were performed in 197 patients 4 to 82 years old, comprising 78 nephrectomies, 50 renal cyst resections, 14 nephropexies, 11 ureterolyses, 8 retroperitoneal lymph node dissections, 8 renal biopsies, 6 adrenalectomies, 6 heminephrectomies, 6 pyeloplasties, 5 ureterolithotomies, 6 ureterocutaneostomies and 2 others. Of the patients 38 (19%) and 22 (11%) had undergone previous abdominal surgery, and kidney and ureter operations, respectively. Dissection of the retroperitoneal space was enabled by the use of a balloon catheter in 14, balloon trocar system in 93 and finger dissection technique in 93 cases. RESULTS: We classified 76 procedures (38%) as simple (renal biopsy, renal cyst resections, ureterocutaneostomy), 102 (51%) as difficult (adrenalectomy, nephrectomy, nephropexy) and 22 (11%) as very difficult (pyeloplasty, heminephrectomy, lymphadenectomy). There was a significant learning curve during the first 50 cases reflected by longer operating time, and higher complication, conversion to open surgery and open reintervention rates (14, 10 and 6%, respectively). In addition to the learning curve, mean operating time depended on the difficulty of the procedure, averaging 45 to 100 minutes for a simple, 95 to 185 for a difficult and 185 to 240 for a very difficult retroperitoneoscopy. In the last 50 cases the complication, conversion and reintervention rates (2, 4 and 2%, respectively) were acceptable for routine clinical application. CONCLUSIONS: After experience with more than 200 cases of retroperitoneoscopy the access technique has been significantly simplified. The procedure is standardized, safe and reproducible.     

The current status of adjuvant hormonal therapy combined with radiation therapy for localised prostate cancer

The limbic system comprises the hippocampal formation, fornix, mamillary bodies, thalamus, and other integrated structures. It is involved in complex functions including memory and emotion and in diseases such as temporal lobe epilepsy. Volume measurements of the amygdala and hippocampus have been used reliably to study patients with temporal lobe epilepsy but have not extended to other limbic structures. We performed volume measurements of hippocampus, amygdala, fornix and mamillary bodies in healthy individuals. Measurements of the amygdala, hippocampus, fornix and mamillary bodies revealed significant differences in volume between right and left sides (P < 0.001). The intraclass coefficient of variation for measurements was high for all structures except the mamillary bodies. Qualitative image assessment of the same structures revealed no asymmetries between the hemispheres. This technique can be applied to the study of disorders affecting the limbic system.     

Pathological staging and biochemical recurrence after neoadjuvant androgen deprivation therapy in combination with radical prostatectomy in clinically localized prostate cancer: results of a phase II study

OBJECTIVES: To assess the pathological staging and biochemical progression-free survival (assessed using serum prostate-specific antigen level) of patients with clinically localized prostate cancer using neoadjuvant androgen deprivation therapy (ADT) in combination with radical retropubic prostatectomy (RRP). PATIENTS AND METHODS: A prospective study was carried out on 69 patients with localized prostate cancer who were enrolled in a trial of 3 months of ADT followed by RRP (group 1). These patients were compared with 72 patients matched for age and clinical stage who declined ADT therapy and had RRP concurrently (group 2). Assignment to the individual treatment groups was thus determined by the patient's preference and not the physician's selection. Pathological staging and biochemical progression-free recurrence were compared between the groups. RESULTS: The rate of organ-confined (pT2) tumours was 74% in group 1 and 49% in group 2 (P < 0.01), and the rate of margin-negative tumours was 87% in group 1 and 64% in group 2 (P < 0.01). Within a median follow-up of 35 months, there was no significant difference in biochemical failure between the groups (P = 0.37). Patients with pT2 disease, regardless of treatment, had similar biochemical failure rates. In the patients with margin-positive disease, there was a significantly higher biochemical failure rate in group 1 (P = 0.02). CONCLUSIONS: The rates of organ- and specimen-confined disease were higher among the patients treated with ADT. The preliminary follow-up suggested that patients with pT2 disease after ADT have a biochemical progression-free recurrence rate similar to pT2 patients treated with RRP alone. Additionally, high biochemical failure rates in patients with margin-positive disease after ADT may identify a subset of more biologically aggressive tumours in need of early adjuvant treatment.     

A "distant" bystander effect of suicide gene therapy: regression of nontransduced tumors together with a distant transduced tumor

Antitumor gene therapy using herpes simplex type 1 thymidine kinase (TKh) and ganciclovir (GCV) treatment has revealed an important intratumoral bystander effect. A whole tumor can be eliminated when only a fraction of its tumor cells express TKh. We now report that the bystander effect not only acts within a tumor, but also between distant tumors. One TKh+ tumor was generated simultaneously with one or multiple TKh- tumors in different rat liver lobes such that there was no contact between the resulting tumors. Both the TKh+ and the TKh- tumors regressed after GCV treatment and showed infiltration with macrophages and T lymphocytes. This distant bystander effect, which is likely immune mediated, should be of major importance for gene therapy of disseminated tumors.     

The surgical therapy of prostatic tumors]

A random sample of 26,000 Swedish women who were asked about their smoking habits in the early 1960s have now been followed for 26 years with respect to cancer incidence. Most findings regarding tobacco smoking and cancer from studies of men were confirmed also among the women. Elevated relative risk for current smokers compared with women who never smoked regularly were seen for cancers of the lung, upper aerodigestive sites, pancreas, bladder, cervix and all cancers combined, as well as a notably high relative risk for cancers of organs of the urinary tract other than kidney and bladder. Relative risk increased with dose, measured as grams of tobacco smoked per day, for cancers of the upper aerodigestive sites, lung, cervix, bladder, organs of the urinary tract other than kidney and bladder and all cancers combined. For cancers of the lung, bladder and cervix, there was an inverse relationship with age when starting to smoke tobacco. The reported inverse relationship between smoking and endometrial cancer could not be corroborated, nor was there any significant relationship between smoking and colorectal or breast cancer.     

Fractal characteristics of tumor vascular architecture during tumor growth and regression

BACKGROUND AND OBJECTIVE: Class III periodontal furcations still represent a challenge for the periodontist. Aim of this study was to test the effect of CO2 laser on the treatment of class III furcation defects. STUDY DESIGN/MATERIALS AND METHOD: Class III furcation defects 3 mm deep were surgically induced on mandibular premolars on six male Beagle dogs, for a total of 36 defects. After 6-8 weeks of plaque accumulation, the mean depth was 6.8 mm. Quadrants were randomly assigned to a) CO2 laser therapy (laser), b) Guided Tissue Regeneration (GTR) procedure using Gore-Tex Membranes, (Gore Tex, Flagstaff, Arizona, USA) and c) Scaling and Root planing (Sc/Rp). CO2 laser beam (El.En, Florence, Italy) was applied to the root surfaces in defocused pulsed mode at 2W, 1 Hz and a duty cycle of 6%, and on periodontal soft tissues at 13W, 40 Hz, and a duty cycle of 40%. Control quadrants received either GTR procedure or Sc/Rp. Mechanical oral hygiene was provided. At 6 months the animals were sacrificed. RESULTS: The laser group showed new attachment formation averaging 1.9 mm (sd +/- 0.5), whereas GTR and Sc/Rp showed 0.2 mm (sd +/- 0.4) and 0.2 mm (sd +/- 0.5) respectively, being the differences statistically significant between the laser group and both GTR and Sc/Rp groups (p < 0.005). CONCLUSION: CO2 laser treatment of class III furcation induced formation of new periodontal ligament, cementum and bone.     

Early tumor cell dissemination in patients with clinically localized carcinoma of the prostate

Death-associated protein kinase (DAP kinase) has been recently identified as a novel Ca2+/calmodulin-dependent protein kinase and as a potential mediator of gamma interferon-induced cell death of Hela cells, which has cytological characteristics of the programmed cell death. In order to elucidate its functional roles in the rat brain where the programmed cell death is an essential mechanism in the organization of postmitotic neurons during development, we cloned a rat homologue of the human DAP kinase from the rat embryonic brain cDNA library. The deduced amino acid sequence was highly conserved between the two species (93.6%). By in situ hybridization histochemistry, the expression of DAP kinase mRNA was observed in the mantle and ventricular zones of the entire neuraxis on embryonic day 15. However, the overall expression in the brain decreased markedly after birth and the expression was maintained at substantial levels in several restricted mature neuronal populations, such as olfactory bulb, hippocampal formation and cerebellar Purkinje and granule cells. Its wide expression during development and its maintained expression in the restricted mature neuronal population suggest that DAP kinase might be involved in some neuronal functions beyond simply executing the developmental neuronal cell death.     

In vitro regulation of pericellular proteolysis in prostatic tumor cells treated with bombesin

Bombesin is a potent inducer of signal trasduction pathways involved in the proliferation and invasion of androgen-insensitive prostatic tumor cells. This study examines the bombesin-mediated modulation of pericellular proteolysis, monitoring cell capability to migrate and invade basement membranes, using a chemo-invasion assay and analyzing protease production. The results suggest that bombesin could modulate the invasive potential of prostatic cell lines regulating secretion and cell-surface uptake of uPA and MMP-9 activation. In fact, in PC3 and DU145 cells but not in LNCaP cells, urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) are induced by bombesin treatment. Bombesin also stimulates cell proliferation and this effect can be inhibited blocking uPA by antibodies and/or uPA inhibitor p-aminobenzamidine. Moreover, HMW-uPA induces cell proliferation in LNCaP cells, which do not produce uPA in the basal conditions, while PC3 and DU145 cell growth is supported by autocrine production of uPA. The increment of uPA activity on the external plasma membrane causes an increased pericellular plasmin activation. This effect is inhibited by antibodies against uPA and by p-aminobenzamidine. Similarly to EGF, bombesin stimulates secretion and activation of MMP-9 and TIMP-1 production. MMP-9 activation can be also obtained by HMW-uPA treatment, suggesting that plasma-membrane-bound uPA can start a proteolytic cascade involving MMP-9. Therefore, in in vitro assays, bombesin is able to modulate pericellular proteolysis and cell proliferation, differently distributing and activating proteolytic activities. This effect can be related to the "non-random" degradation of the extracellular matrix in which membrane uPA-uPAreceptor complexes could start bombesin-induced directional protein degradation during metastatic spread.     

Systematic sextant biopsies improve preoperative prediction of pelvic lymph node metastases in patients with clinically localized prostatic carcinoma

PURPOSE: An algorithm including the results of systematic sextant biopsies was statistically developed and evaluated to predict the probability of pelvic lymph node metastases in patients with clinically localized carcinoma of the prostate. MATERIALS AND METHODS: Clinical stage, serum prostate specific antigen concentration, Gleason score, number of positive biopsies, number of biopsies containing any Gleason grade 4 or 5 cancer and number of biopsies predominated by Gleason grade 4 or 5 cancer were recorded in 345 patients undergoing pelvic lymph node dissection and correlated with the incidence of lymph node metastases. Multivariate logistic regression, and classification and regression trees analyses were performed. RESULTS: In univariate analysis all variables had a statistically significant influence on lymph node status. Logistic regression showed that the amount and distribution of undifferentiated Gleason grade 4 and 5 cancer in the biopsies were the best predictors of lymphatic spread followed by serum prostate specific antigen. Classification and regression trees analysis classified 79.9% of patients who had 3 or fewer biopsies with Gleason grade 4 or 5 cancer and no biopsies predominated by undifferentiated cancer as a low risk group. In this group positive lymph nodes occurred in only 2.2% (95% confidence interval 0.8 to 4.7%). CONCLUSIONS: Including the results of systematic sextant biopsies substantially enhances the predictive accuracy of algorithms that define the probability of lymph node metastases in prostatic cancer. Patients thus defined as having no lymphatic spread could potentially be spared pelvic lymph node dissection before definitive local treatment.     

前列腺癌的中医药辅助治疗概况

前列腺癌是男性常见的恶性肿瘤之一,其在欧美地区发病率占男性肿瘤第1位,病死率为第2位[1].在我国其发病率、死亡率也呈逐年上升趋势[2].前列腺癌发病隐蔽,不易早期诊断,目前虽然西医治疗该病已经有了很大突破,并有了多种治疗手段及方法,显著延长了患者生存期,但是在对患者生活质量及生存质量的改善方面,还存在着很多缺憾.近年来研究表明,中医采用整体辨证辅助治疗前列腺癌,在提高生活质量、延长生存期等方面显示出了较好的前景[3].