Clinical presentation and initial management of black men and white men with prostate cancer in the United Kingdom: the PROCESS cohort study.

BACKGROUND: In the United States, Black men have a higher risk of prostate cancer and worse survival than do White men, but it is unclear whether this is because of differences in diagnosis and management. We re-examined these differences in the United Kingdom, where health care is free and unlikely to vary by socioeconomic status. METHODS: This study is a population-based retrospective cohort study of men diagnosed with prostate cancer with data on ethnicity, prognostic factors, and clinical care. A Delphi panel considered the appropriateness of investigations and treatments received. RESULTS: At diagnosis, Black men had similar clinical stage and Gleason scores but higher age-adjusted prostate-specific antigen levels (geometric mean ratio 1.41, 95% confidence interval (95% CI): 1.15-1.73). Black men underwent more investigations and were more likely to undergo radical treatment, although this was largely explained by their younger age. Even after age adjustment, Black men were more likely to undergo a bone scan (odds ratio 1.37, 95% CI: 1.05-1.80). The Delphi analysis did not suggest differential management by ethnicity. CONCLUSIONS: This UK-based study comparing Black men with White men found no evidence of differences in disease characteristics at the time of prostate cancer diagnosis, nor of under-investigation or under-treatment in Black men.

Pathways to diagnosis for Black men and White men found to have prostate cancer: the PROCESS cohort study.

Black men in England have three times the age-adjusted incidence of diagnosed prostate cancer as compared with their White counterparts. This population-based retrospective cohort study is the first UK-based investigation of whether access to diagnostic services underlies the association between race and prostate cancer. Prostate cancer was ascertained using multiple sources including hospital records. Race and factors that may influence prostate cancer diagnosis were assessed by questionnaire and hospital records review. We found that Black men were diagnosed an average of 5.1 years younger as compared with White men (P<0.001). Men of both races were comparable in their knowledge of prostate cancer, in the delays reported before presentation, and in their experience of co-morbidity and symptoms. Black men were more likely to be referred for diagnostic investigation by a hospital department (P=0.013), although general practitioners referred the large majority of men. Prostate-specific antigen levels were comparable at diagnosis, although Black men had higher levels when compared with same-age White men (P<0.001). In conclusion, we found no evidence of Black men having poorer access to diagnostic services. Differences in the run-up to diagnosis are modest and seem insufficient to explain the higher rate of prostate cancer diagnosis in Black men.

Expression of growth factor and epidermal growth factor receptor encoded transcripts in human gastric tissues.

Expression of mRNA-encoding transforming growth factors alpha and beta (TGF alpha and beta), epidermal growth factor receptor (EGFR), and platelet-derived growth factors (PDGF) A and B chains was examined in 63 human gastric biopsies. Despite considerable individual variation, transcript levels were generally higher in 16 paired gastric tumors compared with surrounding epithelium. Marked increases were observed for the TGFs and c-sis, whereas EGFR mRNA was poorly expressed; there was no correlation with pathological staging of the cancers. In the nonneoplastic tissues, 14 had normal histology and 27 displayed superficial (SG) or atrophic gastritis (AG). Transcript levels greater than or equal to + were similar between these categories for all the growth factors, but were about 50% higher for EGFR in the tissues with gastritis. Concurrent expression of TGF alpha and EGFR (greater than or equal to + level) was more frequent in the paired tumors (38%) than in adjacent nonmalignant tissue (6%) and was seen in only one of 14 (7%) normal samples, in three of 19 (16%) of those with AG, and none of eight of those displaying SG. High levels of TGF beta and PDGFA mRNA were expressed in gastric ulcers, with little or no TGF alpha and EGFR transcripts; in contrast both TGFs and EGFR message were found in normal oesophagus. Stomach tissues are thus capable of synthesizing a variety of growth factors. These may be associated with nonneoplastic hyperplasia and/or malignant proliferation. Coexpression of TGF alpha/EGFR supports the possibility of an autocrine loop sustaining tumor growth which is different from the mechanisms responsible for normal cellular proliferation.

Prostatic intraepithelial neoplasia: a risk factor for prostate cancer.

Prostatic Intraepithelial Neoplasia (PIN) is an increasingly common finding at ultrasound guided prostate biopsy, with the high grade form (HGPIN) thought to be "precancerous". With the more widespread use of extended biopsy protocols, taking sometimes up to 14 cores or more, the incidence of HGPIN can be up to 25%. Histologically, it has many features in common with cancer of the prostate and has been shown to be both associated with cancer at the time of its finding and predictive for the development of prostate cancer in the future. Basic science research has demonstrated genes common specifically to both prostate cancer and HGPIN and immunostaining studies of microvessel density may help to differentiate HGPIN from lower risk PIN. There are no active treatments for HGPIN although there are trials to assess the effectiveness of hormonal therapy and nutritional supplements. Currently most urologists recommend that patients should be followed at 6 monthly intervals with regular PSA and repeat biopsies as indicated.

Creatine kinase MB isoforms: a potential predictor of acute cardiac allograft rejection.

BACKGROUND: Noninvasive studies to detect or predict acute allograft rejection after heart transplantation have failed to be sufficiently reliable to substitute for endomyocardial biopsy. Isoforms of creatine kinase MB isoenzyme (MB2 and MB1) are extremely sensitive markers of ischemic myocardial damage and, in theory, may be elevated in cardiac allograft rejection when myocardial necrosis is visible on microscopy (International Society for Heart and Lung Transplantation grade 2 or greater). METHODS: We examined, prospectively, the endomyocardial biopsy specimens (n = 256) of 50 consecutive patients undergoing orthotopic heart transplantation. Blood samples for creatine kinase MB isoforms (n = 527) were taken immediately before endomyocardial biopsy and at intervals between biopsies. RESULTS: The median ratio of MB2/MB1 in plasma samples taken at the time of biopsy for grades 2 and 3 was not significantly different from the ratio from biopsy specimens graded 0 and 1 (1.65 versus 1.33; p = Not significant). The sensitivity for diagnosing a moderately severe rejection was 47% with a specificity of 58%. However, in patients with significant acute rejection (grades 2 and 3) in whom consecutive samples were collected, the MB2/MB1 ratio was significantly increased before histologic changes seen on biopsy in 13 of 16 rejection episodes by a mean of 14 days. The sensitivity for predicting rejection (grade 2 or 3) before endomyocardial biopsy was 60% with a specificity of 71% (positive predictive value 43%, negative predictive value 86%). CONCLUSIONS: Creatine kinase MB isoforms may predict the occurrence of acute rejection before histologic evidence seen on endomyocardial biopsy.

Microbial flora of the vagina and cervix.

The microbial flora of the vagina and cervix was assessed qualitatively and semiquantitatively in 40 women attending an intrauterine contraceptive device clinic. Both sites harboured many types of macroorganism, the mean number of microbial types isolated being five from the vagina and four from the cervix. Typical lactobacilli were detected in 61% of vaginal and in 53% of cervical specimens; faecal bacteria, including anaerobes, were even more frequently found at both sites. No differences in the microbial populations at either the vagina or the cervix were detected after fitting of the devices, in the different weeks of the menstrual cycle, or with various previously used contraceptive methods.

Use of endoscopic biopsy for diagnosing congestive gastropathy.

The specificity of endoscopic biopsy specimens in diagnosing congestive gastropathy in 20 patients with portal hypertension, 20 patients with liver disease without portal hypertension, and 20 patients with a normal stomach at endoscopy without liver disease was examined. Histological assessment, which was performed without knowledge of the clinical details, showed changes previously reported to be indicative of congestive gastropathy in 9 (47%) of patients with portal hypertension. Similar changes were also seen in 17 (85%) of patients with liver disease without portal hypertension and in 16 (84%) of patients with normal endoscopies without liver disease. These results show that the histological changes seen in endoscopic biopsy specimens of congestive gastropathy are not specific for this condition and therefore cannot be used to diagnose objectively the disease or assess management.

The prognostic value of argyrophil nucleolar organiser regions (AgNORs) in colorectal cancer.

Argyrophil nucleolar organiser regions (AgNORs) are increased in a variety of malignant cells compared with normal cells, and a recent study has claimed that AgNORs have prognostic value in colorectal cancer. We have studied the AgNOR counts in tumours from 95 colonic resections performed in 94 patients in whom a minimum 5 year follow-up was available. In 71 pathological specimens adjacent normal mucosa was also examined. There was a significant difference between AgNORs per cell in normal mucosa (median 1.46, range 1.10-1.80) compared with tumour cells (median 1.92, range 1.42-2.95, P less than 0.001). There were no significant differences in average AgNORs per cell between tumours in each Dukes' stage or category of differentiation. The average AgNORs per cell in tumours of patients surviving disease-free for 5 years was the same as that in tumours of patients dying of colonic cancer recurrence. We conclude that AgNORs have no prognostic value in colorectal cancer and are not correlated with Dukes' staging or differentiation of the tumour.

Increased production of growth factors and epidermal growth factor receptor by gastric carcinoma.

Four growth factors and one growth factor receptor have been studied in carcinomas from 22 gastrectomy specimens and compared to non-malignant tissue from the same specimen. cDNA probes for transforming growth factors alpha and beta, platelet-derived growth factor A and B, insulin-like growth factor II and epidermal growth factor receptor were used to assay messenger RNA transcripts for the growth factors by dot hybridization. Increased levels of all the transcripts were found in carcinomas compared to benign tissue (P less than 0.05). No correlation was found between any of the growth factors studied and tumour stage or patient survival. Increased growth factor production by gastric cancers may be important in the pathogenesis of these tumours and further work is required to establish their role.

The importance of the resection margin in conservative surgery for breast cancer.

Eradication of breast cancer by wide local excision alone is not possible unless the clinical margins of excision exceeds 5 cm or a segmental mastectomy is performed, though recurrences may still occur after a segmental mastectomy. With inadequate excision radiotherapy to the breast is essential, but will not prevent local recurrence. In a prospective trial (1981 to 1990) to assess the value of radiotherapy to the breast when adjuvant therapy was administered, 418 patients treated by wide local excision and adjuvant chemotherapy (tamoxifen if oestrogen receptor-positive and CMF chemotherapy if oestrogen receptor-negative) were randomized to have loco-regional radiotherapy to the breast or not. At a minimum 5-year follow-up, the local recurrence rate in patients receiving radiotherapy was 13% compared to 35% in those not so treated. Local recurrence was strictly related to microscopic clearance in millimetres irrespective of clinical wide local excision, nodal, or menopausal status. Where, histologically, local excision was incomplete and patients received radiotherapy, the local recurrence rate was 17%. The criteria for wide local excision need to be strictly defined and histologically proven if post-operative radiotherapy is to achieve its effective function, that is the prevention of local recurrence. Radiotherapy cannot compensate for inadequate surgery.

Potential improvements in the therapeutic ratio of prostate cancer irradiation: dose escalation of pathologically identified tumour nodules using intensity modulated radiotherapy.

The potential of intensity modulated radiotherapy (IMRT) to improve the therapeutic ratio in prostate cancer by dose escalation of intraprostatic tumour nodules (IPTNs) was investigated using a simultaneous integrated boost technique. The prostate and organs-at-risk were outlined on CT images from six prostate cancer patients. Positions of IPTNs were transferred onto the CT images from prostate maps derived from sequential large block sections of whole prostatectomy specimens. Inverse planned IMRT dose distributions were created to irradiate the prostate to 70 Gy and all the IPTNs to 90 Gy. A second plan was produced to escalate only the dominant IPTN (DIPTN) to 90 Gy, mimicking current imaging techniques. These plans were compared with homogeneous prostate irradiation to 70 Gy using dose-volume histograms, tumour control probability (TCP) and normal tissue complication probability (NTCP) for the rectum. The mean dose to IPTNs was increased from 69.8 Gy to 89.1 Gy if all the IPTNs were dose escalated (p=0.0003). This corresponded to a mean increase in TCP of 8.7-31.2% depending on the alpha/beta ratio of prostate cancer (p<0.001), and a mean increase in rectal NTCP of 3.0% (p<0.001). If only the DIPTN was dose escalated, the TCP was increased by 6.4-27.5% (p<0.003) and the rectal NTCP was increased by 1.8% (p<0.01). In the dose escalated DIPTN IMRT plans, the highest rectal NTCP was seen in patients with IPTNs in the posterior peripheral zone close to the anterior rectal wall, and the lowest NTCP was seen with IPTNs in the lateral peripheral zone. The ratio of increased TCP to NTCP may represent an improvement in the therapeutic ratio, but was dependent on the position of the IPTN relative to the anterior rectal wall. Improvements in prostate imaging and prostate immobilization are required before clinical implementation would be possible. Clinical trials are required to confirm the clinical benefits of these improved dose distributions.

Signet ring cell carcinoma in the prostate.

Metastases to the prostate gland are rare and often found in the context of widespread metastatic disease. We report an unusual case of primary gastric signet ring cell adenocarcinoma (SRCC) diagnosed over 1 year after treatment for metastatic disease in the prostate.

Progression of gastric mucosal dysplasia of the postgastrectomy stomach.

Gastric cancer, if diagnosed at the symptomatic stage, has a poor prognosis, with an overall 5 year survival of about 5%. The surgical treatment of early gastric cancer increases this 5-year survival rate to 90%. In Japan, endoscopic surveillance has increased the proportion of gastric cancer detected at an early stage from 15% in 1960 to 50% in 1985, and the overall 5 year survival has been increased from 35% to 70%. Mass screening in Japan is worthwhile because the incidence of gastric cancer is about 80 cases per 100,000 population per annum (age standardized). But in other countries where the incidence is much lower the case for mass screening is weak and selective screening of those at high risk is advocated.

Progression of Gastric Mucosal Dysplasia of the Postgastrectomy Stomach.

Gastric cancer, if diagnosed at the symptomatic stage, has a poor prognosis, with an overall 5 year survival of about 5%. The surgical treatment of early gastric cancer increases this 5-year survival rate to 90%. In Japan, endoscopic surveillance has increased the proportion of gastric cancer detected at an early stage from 15% in 1960 to 50% in 1985, and the overall 5 year survival has been increased from 35% to 70%. Mass screening in Japan is worthwhile because the incidence of gastric cancer is about 80 cases per 100,000 population per annum (age standardized). But in other countries where the incidence is much lower the case for mass screening is weak and selective screening of those at high risk is advocated.

Small bowel complications of metastatic lung carcinoma.

A case of small bowel perforation and a case of small bowel obstruction as a result of metastatic lung carcinoma are presented. The surgical management of each is discussed. The patient who presented with small bowel perforation died in the immediate post-operative period, while the patient who presented with small bowel obstruction is alive and well six months later. Patients with primary lung carcinoma who present with an acute abdomen should be treated by standard surgical principles irrespective of their primary pathology.

Clinicopathological and molecular study of penile melanoma.

AIMS: To examine the clinicopathological features of a series of penile melanomas and screen for mutations in the BRAF and KIT genes, which are seen in melanomas from other sites. METHODS AND RESULTS: 12 patients with penile melanoma were identified over a 10-year period in two supra-regional networks in the UK. The 2- and 5-year survival was 61% and 20%, respectively. Half the patients had lymph node involvement at presentation; this was a poor prognostic indicator. KIT exons 11, 13, 17 and 18, and BRAF codons 600 and 601 were analysed for mutations by Sanger sequencing and pyrosequencing, respectively. None of the tumours showed either KIT mutations or the BRAF V600E mutation. CONCLUSION: Penile melanomas are extremely rare and have a similar prognosis to melanomas elsewhere, but they often present late, leading to a poor outcome. The mutations seen in melanomas from other sites appear to be rarely present in these tumours.

Sentinel lymph node biopsy using dynamic lymphoscintigraphy combined with ultrasound-guided fine needle aspiration in penile carcinoma.

The purpose of this study was to assess the utility of sentinel lymph node lymphoscintigraphy (SLNL) and ultrasound-guided fine needle aspiration cytology (FNAC) in patients with penile carcinoma. A prospective study was undertaken of 64 patients with stage T1 (or greater) clinically N0 squamous cell carcinoma of the penis. Patients underwent SLNL and bilateral groin ultrasonography with or without FNAC. Following intradermal blue dye, patients underwent unilateral or bilateral sentinel lymph node excision biopsy (SNB). 17 patients had sentinel nodes that contained metastases (21 nodal basins). Lymphatic drainage was demonstrated in all patients by lymphoscintigraphy. Bilateral drainage was seen in 57/64 patients. 61/64 patients had ultrasonography of the inguinal basins on the same day as FNAC of 38 basins. FNAC showed malignancy in eight basins. FNAC was negative in six basins, which were subsequently shown to be positive following SNB. 82 inguinal basins did not warrant FNAC by ultrasound criteria, of which 5 contained metastases at SNB. The sensitivity and specificity of ultrasonography was 74% and 77%, respectively. The positive and negative predictive values were 37% and 94%, respectively. Two patients had a negative initial SNB; however, ultrasonography identified a metastatic node and re-evaluation of the sentinel node confirmed micro-metastases. There has been no evidence of recurrence in any patients with negative SNB (during 6-28 months' follow-up). In conclusion, when investigating clinically stage N0 penile cancer, the combination of SNB and groin ultrasonography, with or without FNAC, identifies accurately those with occult nodal metastases. Ultrasonography alone is not adequate as a staging technique, and SNB alone might miss between 5% and 10% of metastases.

Biopsy tissue microarray study of Ki-67 expression in untreated, localized prostate cancer managed by active surveillance.

Active surveillance provides a unique opportunity to study biomarkers of prostate cancer behaviour, although only small volumes of tumor tissue are typically available. We have evaluated a technique for constructing tissue microarrays (TMAs) from needle biopsies for assessing immunohistochemical markers in localized prostate cancer managed by active surveillance. TMAs were constructed from diagnostic prostate biopsies for 60 patients with localized prostatic adenocarcinoma in a prospective cohort study of active surveillance. Radical treatment was recommended for a prostate-specific antigen (PSA) velocity greater than 1 ng ml(-1) per year or adverse histology in repeat biopsies, defined as Gleason score > or =4+3 or >50% of cores involved. Sections from the TMAs were stained with H&E, P63/AMACR and Ki-67. Time to radical treatment was analysed with respect to clinical characteristics and Ki-67 LI. At a median follow up of 36 months, 25/60 (42%) patients had received radical treatment. On univariate analysis, PSA density (P=0.001), Gleason score (P=0.001), clinical T stage (P=0.01), Ki-67 LI (P=0.02) and initial PSA (P=0.04) were associated with time to radical treatment. On multivariate analysis, PSA density (P=0.01), Ki-67 LI (P=0.03) and Gleason score (P=0.04) were independent determinants of progression to radical treatment. TMAs constructed from prostate needle biopsies can be used to assess immunohistochemical markers in localized prostate cancer managed by active surveillance. Ki-67 LI merits further study as a possible biomarker of early prostate cancer behaviour.

Dynamic contrast-enhanced MRI for prostate cancer localization.

Radiotherapy dose escalation improves tumour control in prostate cancer but with increased toxicity. Boosting focal tumour only may allow dose escalation with acceptable toxicity. Intensity-modulated radiotherapy can deliver this, but visualization of the tumour remains limiting. CT or conventional MRI techniques are poor at localizing tumour, but dynamic contrast-enhanced MRI (DCE-MRI) may be superior. 18 patients with prostate cancer had T(2) weighted (T2W) and DCE-MRI prior to prostatectomy. The prostate was sectioned meticulously so as to achieve accurate correlation between imaging and pathology. The accuracy of DCE-MRI for cancer detection was calculated by a pixel-by-pixel correlation of quantitative DCE-MRI parameter maps and pathology. In addition, a radiologist interpreted the DCE-MRI and T2W images. The location of tumour on imaging was compared with histology, and the accuracy of DCE-MRI and T2W images was then compared. Pixel-by-pixel comparison of quantitative parameter maps showed a significant difference between the benign peripheral zone and tumour for the parameters K(trans), v(e) and k(ep). Calculation of areas under the receiver operating characteristic curve showed that the pharmacokinetic parameters were only "fair" discriminators between cancer and benign gland. Interpretation of DCE-MRI and T2W images by a radiologist showed DCE-MRI to be more sensitive than T2W images for tumour localization (50% vs 21%; p = 0.006) and similarly specific (85% vs 81%; p = 0.593). The superior sensitivity of DCE-MRI compared with T2W images, together with its high specificity, is arguably sufficient for its use in guiding radiotherapy boosts in prostate cancer.