Malignant spinal cord compression: NICE guidance, improvements and challenges.

BACKGROUND AND AIM: Malignant spinal cord compression (mSCC) is one of the most serious complications of cancer. Recent NICE guidance has aimed to improve patient pathways and outcomes for patients with mSCC. We have examined the current presentations, management and outcomes for patients with mSCC in West London following the implementation of the NICE guidance. MATERIALS AND METHODS: The electronic records and clinical notes were reviewed for all patients assessed for confirmed or potential mSCC at Charing Cross Hospital in 2012. Details on the number of referrals, the proportion with confirmed mSCC, the cancer diagnosis, treatment and outcome were analysed. RESULTS: 191 patients were reviewed with 127 (66%) cases of confirmed mSCC. The commonest tumour types were prostate cancer (26 cases), lung cancer (26), breast cancer (21) and kidney cancer (15). 21% of the patients had no previous cancer diagnosis; mSCC was their presenting diagnostic event. Radiotherapy was the predominant management, 24% of the patients had first line surgical treatment. At presentation 62% of patients were either chair or bed bound. Treatment brought important mobility benefits to all patients groups with 20% of the initially chair or bed bound patients leaving the hospital with independent mobility. CONCLUSION: Enhanced patients pathways with ease of access, rapid assessment and prompt treatment can improve outcomes. Despite these pathways many patients still present with gross motor impairment and over 20% have no previous diagnosis of cancer. Ongoing work to maintain awareness for patients and primary care of the diagnosis and emergency pathways is essential to optimize outcomes.

Targeted prostate cancer screening in men with mutations in BRCA1 and BRCA2 detects aggressive prostate cancer: preliminary analysis of the results of the IMPACT study.

OBJECTIVE: To evaluate the role of targeted prostate cancer screening in men with BRCA1 or BRCA2 mutations, an international study, IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls), was established. This is the first multicentre screening study targeted at men with a known genetic predisposition to prostate cancer. A preliminary analysis of the data is reported. PATIENTS AND METHODS: Men aged 40-69 years from families with BRCA1 or BRCA2 mutations were offered annual prostate specific antigen (PSA) testing, and those with PSA > 3 ng/mL, were offered a prostate biopsy. Controls were men age-matched (± 5 years) who were negative for the familial mutation. RESULTS: In total, 300 men were recruited (205 mutation carriers; 89 BRCA1, 116 BRCA2 and 95 controls) over 33 months. At the baseline screen (year 1), 7.0% (21/300) underwent a prostate biopsy. Prostate cancer was diagnosed in ten individuals, a prevalence of 3.3%. The positive predictive value of PSA screening in this cohort was 47·6% (10/21). One prostate cancer was diagnosed at year 2. Of the 11 prostate cancers diagnosed, nine were in mutation carriers, two in controls, and eight were clinically significant. CONCLUSIONS: The present study shows that the positive predictive value of PSA screening in BRCA mutation carriers is high and that screening detects clinically significant prostate cancer. These results support the rationale for continued screening in such men.

Prostate cancer in BRCA2 germline mutation carriers is associated with poorer prognosis.

BACKGROUND: The germline BRCA2 mutation is associated with increased prostate cancer (PrCa) risk. We have assessed survival in young PrCa cases with a germline mutation in BRCA2 and investigated loss of heterozygosity at BRCA2 in their tumours. METHODS: Two cohorts were compared: one was a group with young-onset PrCa, tested for germline BRCA2 mutations (6 of 263 cases had a germline BRAC2 mutation), and the second was a validation set consisting of a clinical set from Manchester of known BRCA2 mutuation carriers (15 cases) with PrCa. Survival data were compared with a control series of patients in a single clinic as determined by Kaplan-Meier estimates. Loss of heterozygosity was tested for in the DNA of tumour tissue of the young-onset group by typing four microsatellite markers that flanked the BRCA2 gene, followed by sequencing. RESULTS: Median survival of all PrCa cases with a germline BRCA2 mutation was shorter at 4.8 years than was survival in controls at 8.5 years (P=0.002). Loss of heterozygosity was found in the majority of tumours of BRCA2 mutation carriers. Multivariate analysis confirmed that the poorer survival of PrCa in BRCA2 mutation carriers is associated with the germline BRCA2 mutation per se. CONCLUSION: BRCA2 germline mutation is an independent prognostic factor for survival in PrCa. Such patients should not be managed with active surveillance as they have more aggressive disease.

TEAD1 and c-Cbl are novel prostate basal cell markers that correlate with poor clinical outcome in prostate cancer.

Prostate cancer is the most frequently diagnosed male cancer, and its clinical outcome is difficult to predict. The disease may involve the inappropriate expression of genes that normally control the proliferation of epithelial cells in the basal layer and their differentiation into luminal cells. Our aim was to identify novel basal cell markers and assess their prognostic and functional significance in prostate cancer. RNA from basal and luminal cells isolated from benign tissue by immunoguided laser-capture microdissection was subjected to expression profiling. We identified 112 and 267 genes defining basal and luminal populations, respectively. The transcription factor TEAD1 and the ubiquitin ligase c-Cbl were identified as novel basal cell markers. Knockdown of either marker using siRNA in prostate cell lines led to decreased cell growth in PC3 and disrupted acinar formation in a 3D culture system of RWPE1. Analyses of prostate cancer tissue microarray staining established that increased protein levels of either marker were associated with decreased patient survival independent of other clinicopathological metrics. These data are consistent with basal features impacting on the development and clinical course of prostate cancers.

The impact of improving outcomes guidance on surgical management of vulval squamous cell cancer in southwest England (1997-2002).

OBJECTIVE: The objective of this study was to assess the impact of reorganisation of gynaecological services in southwest England following adoption of regionally agreed evidence-based guidelines and publication of the National Improving Outcomes Guidance in 1999. DESIGN: Prospective audit with cross-checking against histological reports. SETTING: All 19 acute hospitals in the four Cancer Networks of southwest England. SAMPLE: All subjects with squamous or verrucous vulval cancer diagnosed between 1997 and 2002. METHOD: A one-page minimum data set proforma agreed by the South West Gynaecology Tumour Panel was completed by surgeons after treatment of each patient, and was sent to South West Cancer Intelligence Service for entry, collation and analysis. Data are presented for the years 1997 to 2002 inclusive, and comparisons were made between each of the three 2-year cohorts. MAIN OUTCOME MEASURES: These are standards derived from the guidance. RESULTS: There were 436 squamous or verrucous vulval cancers registered. Recording of staging was missing in 20% of subjects. The percentage of subjects operated upon by lead gynaecological cancer surgeons increased from 78% in cohort 1 to 93% in cohort 3 (P < 0.001). There is a trend towards more conservative operations, which have lower co-morbidity. High activity surgeons achieved better rates of tumour-free skin margins, but even these were adequate only in 49% of operations. Lymphadenectomy rates did not follow guidance. CONCLUSION: Centralisation of care of this rare cancer should continue, but specialists need to increase their efforts to ensure adequate skin margins and lymphadenectomy rates while balancing morbidity and the likelihood of recurrence in both fit and frail patients.

Construction of tissue microarrays from prostate needle biopsy specimens.

Needle biopsies are taken as standard diagnostic specimens for many cancers, but no technique exists for the high-throughput analysis of multiple individual immunohistochemical (IHC) markers using these samples. Here we present a simple and highly reliable technique for constructing tissue microarrays (TMAs) from prostatic needle biopsies. Serial sectioning of the TMAs, called 'Checkerboard TMAs', facilitated expression analysis of multiple proteins using IHC markers. In total, 100% of the analysed biopsies within the TMA both preserved their antigenicity and maintained their morphology. Checkerboard TMAs will allow the use of needle biopsies (i) alongside other tissue specimens (trans-urethral resection of prostates and prostatectomies in the case of prostate cancer) in clinical correlation studies when searching for new prognostic markers, and (ii) in a diagnostic context for assessing expression of multiple proteins in cancers from patients prior to treatment.

Processing of radical prostatectomy specimens for correlation of data from histopathological, molecular biological, and radiological studies: a new whole organ technique.

AIMS: To develop a method of processing non-formalin fixed prostate specimens removed at radical prostatectomy to obtain fresh tissue for research and for correlating diagnostic and molecular results with preoperative imaging. METHODS/RESULTS: The method involves a prostate slicing apparatus comprising a tissue slicer with a series of juxtaposed planar stainless steel blades linked to a support, and a cradle adapted to grip the tissue sample and receive the blades. The fresh prostate gland is held in the cradle and the blades are moved through the cradle slits to produce multiple 4 mm slices of the gland in a plane perpendicular to its posterior surface. One of the resulting slices is preserved in RNAlater. The areas comprising tumour and normal glands within this preserved slice can be identified by matching it to the haematoxylin and eosin stained sections of the adjacent slices that are formalin fixed and paraffin wax embedded. Intact RNA can be extracted from the identified tumour and normal glands within the RNAlater preserved slice. Preoperative imaging studies are acquired with the angulation of axial images chosen to be similar to the slicing axis, such that stained sections from the formalin fixed, paraffin wax embedded slices match their counterparts on imaging. CONCLUSIONS: A novel method of sampling fresh prostate removed at radical prostatectomy that allows tissue samples to be used both for diagnosis and molecular analysis is described. This method also allows the integration of preoperative imaging data with histopathological and molecular data obtained from the prostate tissue slices.

ATM polymorphisms as risk factors for prostate cancer development.

The risk of prostate cancer is known to be elevated in carriers of germline mutations in BRCA2, and possibly also in carriers of BRCA1 and CHEK2 mutations. These genes are components of the ATM-dependent DNA damage signalling pathways. To evaluate the hypothesis that variants in ATM itself might be associated with prostate cancer risk, we genotyped five ATM variants in DNA from 637 prostate cancer patients and 445 controls with no family history of cancer. No significant differences in the frequency of the variant alleles at 5557G>A (D1853N), 5558A>T (D1853V), ivs38-8t>c and ivs38-15g>c were found between the cases and controls. The 3161G (P1054R) variant allele was, however, significantly associated with an increased risk of developing prostate cancer (any G vs CC OR 2.13, 95% CI 1.17-3.87, P=0.016). A lymphoblastoid cell line carrying both the 3161G and the 2572C (858L) variant in the homozygote state shows a cell cycle progression profile after exposure to ionising radiation that is significantly different to that seen in cell lines carrying a wild-type ATM gene. These results provide evidence that the presence of common variants in the ATM gene, may confer an altered cellular phenotype, and that the ATM 3161C>G variant might be associated with prostate cancer risk.

Pregnancy outcomes following treatment of cancer.

While still rare, cancer has the reputation of being life-threatening in all its forms. Coupled with the survival of cancer comes a growing expectation from the patients that their life should be relatively unaffected. Among the side effects, there is frequently an effect on fertility. In particular, the treatment of the young with anti-cancer therapy raises questions about the patient's ability to achieve normal reproductive function and delivery following treatment. Between 1987 and 1998 we identified 40 women who conceived or delivered a fetus following treatment for cancer. They had undergone a combination of therapies including surgery, chemotherapy and radiotherapy. Four had elected to be sterilised after completion of their family. It did not appear from the data collected that the therapy used for treatment of some cancers has had an adverse effect on delivery outcomes, expected weight of the fetus or the gestation of the pregnancy.

Expression of the peptide antibiotics human beta defensin-1 and human beta defensin-2 in normal human skin.

Normal human skin is remarkably resistant to infection from the large numbers of microorganisms that routinely colonize its surface. In addition to the role of skin as a mechanical barrier, it has long been recognized that skin and other epithelia can produce a range of anti-microbial chemicals that play an important part in eliminating potential cutaneous pathogens. Anti-microbial peptides are an important evolutionarily conserved innate host defense mechanism in many organisms. Human beta defensin-1 and -2 are cysteine-rich, cationic, low molecular weight anti-microbial peptides that have recently been shown to be expressed in epithelial tissues. In this study, we describe the characterization of human beta defensin-1 and -2 mRNA and peptide expression in normal human skin. Using reverse transcription-polymerase chain reaction we demonstrate that human beta defensin-1 is consistently expressed in skin samples from various body sites. Human beta defensin-2 demonstrates expression that is more variable and is more readily detectable in facial skin and foreskin compared with skin from abdomen and breast. In situ hybridization localizes the human beta defensin-1 and -2 transcripts to keratinocytes within interfollicular skin. Using specific antibodies, we have shown that human beta defensin-1 and -2 peptides are localized to the Malpighian layer of the epidermis and/or stratum corneum and that there are interindividual and site-specific differences in intensity of immunostaining and the pattern of peptide localization. The localization of human beta defensins to the outer layer of the skin is consistent with the hypothesis that human beta defensins play an essential part in cutaneous innate immunity.

Evaluation of a one-stop clinic for the rapid assessment of post-menopausal bleeding.

In this study, we evaluated the management of postmenopausal bleeding at our one-stop clinic where the first line investigations were a transvaginal ultrasound scan and a pipelle endometrial biopsy. The records of 212 women seen in this clinic in 1994 were reviewed. One hundred and forty-four women (67.9%) were evaluated and reassured in one visit. The mean waiting period following referral to the clinic by the general practitioner was 36 days (range 6-157 days), and only 45 women (21%) required a hysteroscopy. The commonest diagnosis made was endometrial atrophy or no significant endometrial pathology (130 women (61.3%). Endometrial cancer was diagnosed in 12 women (5.6%), and one case of previously unsuspected ovarian cancer was detected. Our findings show that most women with post-menopausal bleeding can be assessed in one visit, and hysteroscopy is not always necessary in the initial assessment of this complaint.

Outpatient diagnostic hysteroscopy.

Outpatient diagnostic hysteroscopy with endometrial sampling was performed in 160 women. The aim was to assess patient acceptance of the procedure when performed under para-cervical block. The most common indication was abnormal uterine bleeding. In 152 patients the procedure was successful, allowing thorough inspection of the uterine cavity, and in almost half of them no abnormality was detected. Thirty-one required subsequent elective admission, mainly for fibroid polypectomy. In most women the level of discomfort was assessed as 'tolerable', but in two the procedure was abandoned because of severe discomfort. Endometrial carcinoma was detected in six patients. There were no complications attributable to the procedure. Outpatient hysteroscopy considerably reduces the need for hospital admission and can provide early investigation for patients with a spectrum of gynaecological disorders, at low cost and with minimal facilities.

Successful pregnancy following bone marrow transplantation for leukaemia.

We report three pregnancies with successful outcomes in two women following allogeneic bone marrow transplantation (BMT) for acute leukaemia using high dose melphalan alone as conditioning therapy. The increasing application and success of BMT together with the instigation of conditioning regimens that do not include total body irradiation should increase such cases. These and previous cases document that a normal outcome of pregnancy is likely in these patients.