Cyril Fisher

Multiple newly identified loci associated with prostate cancer susceptibility

Prostate cancer is the most common cancer affecting males in developed countries. It shows consistent evidence of familial aggregation, but the causes of this aggregation are mostly unknown. To identify common alleles associated with prostate cancer risk, we conducted a genome-wide association study (GWAS) using blood DNA samples from 1,854 individuals with clinically detected prostate cancer diagnosed at ≤60 years or with a family history of disease, and 1,894 population-screened controls with a low prostate-specific antigen (PSA) concentration (<0.5 ng/ml). We analyzed these samples for 541,129 SNPs using the Illumina Infinium platform. Initial putative associations were confirmed using a further 3,268 cases and 3,366 controls. We identified seven loci associated with prostate cancer on chromosomes 3, 6, 7, 10, 11, 19 and X (P = 2.7 × 10−8 to P = 8.7 × 10−29). We confirmed previous reports of common loci associated with prostate cancer at 8q24 and 17q. Moreover, we found that three of the newly identified loci contain candidate susceptibility genes: MSMB, LMTK2 and KLK3.

Perivascular epithelioid cell neoplasms of soft tissue and gynecologic origin : A clinicopathologic study of 26 cases and review of the literature

PEComas, occasionally associated with the tuberous sclerosis complex, are defined by the presence of perivascular epithelioid cells that coexpress muscle and melanocytic markers. This family of tumors includes angiomyolipoma (AML), clear cell sugar tumor of the lung (CCST), lymphangioleiomyomatosis (LAM), and very rare tumors in other locations. Because non-AML/non-LAM PEComas are extremely rare and their natural history and prognostic features undefined, we present our experience with 26 PEComas of soft tissue and the gynecologic tract, the largest series to date. We also performed a detailed review of the literature, with special attention to features predictive of clinical behavior. All PEComas exclusive of AML and LAM were retrieved from our consultation files. Immunohistochemistry for pan-cytokeratin (CK), S-100 protein, smooth muscle actins (SMA), desmin, vimentin, HMB45, Melan-A, microphthalmia transcription factor (MiTF), TFE3, CD117, and CD34 was performed. Clinical follow-up information was obtained. Fishers exact test was performed. The median patient age was 46 years (range, 15-97 years); there was a marked female predominance (22 females, 4 males). Sites of involvement included the omentum or mesentery (6 cases), uterus (4 cases), pelvic soft tissues (3 cases), abdominal wall (2 cases), uterine cervix (2 cases), and vagina, retroperitoneum, thigh, falciform ligament, scalp, broad ligament, forearm, shoulder, and neck (1 case each). The tumors ranged from 1.6 to 29 cm in size (median, 7.8 cm). Tumors were epithelioid (N = 9), spindled (N = 7), or mixed (N = 10). Multinucleated giant cells were present in 18 cases. High nuclear grade was noted in 10 cases, high cellularity in 7 cases, necrosis in 8 cases, and vascular invasion in 3 cases. Mitotic activity was 0 to 50 mitotic figures (MF)/50 high power fields (HPF) (median, 0 MF/50 HPF) with atypical MF in 6 cases. IHC results were: SMA (20/25), desmin (8/22), HMB45 (22/24), Melan-A (13/18), MITF (9/18), S-100 protein (8/24), CK (3/23), vimentin (12/14), TFE3 (5/17), c-kit (1/20), and CD34 (0/7). Clinical follow-up (24 of 26 patients, 92%; median, 30 months; range, 10-84 months) showed 3 local recurrences and 5 distant metastases. At last available clinical follow-up, 2 patients (8%) were dead of disease, 4 patients (17%) were alive with metastatic or unresectable local disease, and 18 patients (75%) were alive with no evidence of disease. No patient in our series had a history of tuberous sclerosis complex. Recurrence and/or metastasis was strongly associated tumor size > median size (8 cm), mitotic activity greater than 1/50 HPF, and necrosis. We conclude that PEComas of soft tissue and gynecologic origin may be classified as “benign,” “of uncertain malignant potential,” or “malignant.” Small PEComas without any worrisome histologic features are most likely benign. PEComas with nuclear pleomorphism alone (“symplastic”) and large PEComas without other worrisome features have uncertain malignant potential. PEComas with two or more worrisome histologic features should be considered malignant. Occasional PEComas express unusual markers, such as S-100 protein, desmin, and rarely CK. The role of TFE3 in PEComas should be further studied.

Kaposi's-sarcoma-associated herpesvirus in HIV-negative Kaposi's sarcoma

events involving, to various degrees, microorganisms such as herpesviruses, hepatitis B virus, HIV, and Mycoplasma penetrans.H Chang and colleagues5 have identified herpesvirus-like DNA sequence in biopsy samples from patients with AIDS-associated KS. This DNA sequence was found exclusively in KS biopsy specimens but not in several other tested tissues. We report our results of screening DNA samples from isolated peripheral blood mononuclear cells (PBMCs). DNA was directly purified from uncultured PBMCs that

Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial

BACKGROUND Effective targeted treatment is unavailable for most sarcomas and doxorubicin and ifosfamide-which have been used to treat soft-tissue sarcoma for more than 30 years-still have an important role. Whether doxorubicin alone or the combination of doxorubicin and ifosfamide should be used routinely is still controversial. We assessed whether dose intensification of doxorubicin with ifosfamide improves survival of patients with advanced soft-tissue sarcoma compared with doxorubicin alone. METHODS We did this phase 3 randomised controlled trial (EORTC 62012) at 38 hospitals in ten countries. We included patients with locally advanced, unresectable, or metastatic high-grade soft-tissue sarcoma, age 18-60 years with a WHO performance status of 0 or 1. They were randomly assigned (1:1) by the minimisation method to either doxorubicin (75 mg/m(2) by intravenous bolus on day 1 or 72 h continuous intravenous infusion) or intensified doxorubicin (75 mg/m(2); 25 mg/m(2) per day, days 1-3) plus ifosfamide (10 g/m(2) over 4 days with mesna and pegfilgrastim) as first-line treatment. Randomisation was stratified by centre, performance status (0 vs 1), age (<50 vs ≥50 years), presence of liver metastases, and histopathological grade (2 vs 3). Patients were treated every 3 weeks till progression or unacceptable toxic effects for up to six cycles. The primary endpoint was overall survival in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, number NCT00061984. FINDINGS Between April 30, 2003, and May 25, 2010, 228 patients were randomly assigned to receive doxorubicin and 227 to receive doxorubicin and ifosfamide. Median follow-up was 56 months (IQR 31-77) in the doxorubicin only group and 59 months (36-72) in the combination group. There was no significant difference in overall survival between groups (median overall survival 12·8 months [95·5% CI 10·5-14·3] in the doxorubicin group vs 14·3 months [12·5-16·5] in the doxorubicin and ifosfamide group; hazard ratio [HR] 0·83 [95·5% CI 0·67-1·03]; stratified log-rank test p=0·076). Median progression-free survival was significantly higher for the doxorubicin and ifosfamide group (7·4 months [95% CI 6·6-8·3]) than for the doxorubicin group (4·6 months [2·9-5·6]; HR 0·74 [95% CI 0·60-0·90], stratified log-rank test p=0·003). More patients in the doxorubicin and ifosfamide group than in the doxorubicin group had an overall response (60 [26%] of 227 patients vs 31 [14%] of 228; p<0·0006). The most common grade 3 and 4 toxic effects-which were all more common with doxorubicin and ifosfamide than with doxorubicin alone-were leucopenia (97 [43%] of 224 patients vs 40 [18%] of 223 patients), neutropenia (93 [42%] vs 83 [37%]), febrile neutropenia (103 (46%) vs 30 [13%]), anaemia (78 [35%] vs 10 [5%]), and thrombocytopenia (75 [33%]) vs one [<1%]). INTERPRETATION Our results do not support the use of intensified doxorubicin and ifosfamide for palliation of advanced soft-tissue sarcoma unless the specific goal is tumour shrinkage. These findings should help individualise the care of patients with this disease. FUNDING Cancer Research UK, EORTC Charitable Trust, UK NHS, Canadian Cancer Society Research Institute, Amgen.

Synovial Sarcoma: A Clinicopathologic, Staging, and Prognostic Assessment

PURPOSE Synovial sarcoma (SS) is a common soft tissue sarcoma (STS) with a propensity for young adults and notable sensitivity to chemotherapy (CT). This study provides a current clinicopathologic, staging, and prognostic assessment for SS. The problems with the current American Joint Committee for Cancer (AJCC) Staging System in relation to SS are discussed. METHODS Review of a prospective database supplemented by retrospective data. RESULTS One hundred fifty patients were assessed; median age was 30 years and median follow-up was 52 months. Overall actuarial 5-year survival rate was 57%. Size trend, but not a cutoff of less than 5 cm versus > or = 5 cm, was a prognostic indicator (P <.001). The current AJCC/International Union Against Cancer Staging System differentiated prognosis less well than the recently proposed Royal Marsden Hospital Staging System. Age greater than 20 years at diagnosis implied worse prognosis. A local recurrence event was associated with a worse survival (P <.001). Therapeutic CT was administered to 55 patients. Eleven of 19 patients had an objective response to a combination of ifosfamide and doxorubicin. Four cases had complete response after CT. Twenty-one patients had pulmonary metastasectomy, with an actuarial 5-year survival rate of 23%. CONCLUSION SS tends to affect young people. In this subtype of STS, size trend is the most significant influence on stage and hence survival; however, smaller SSs have an unexpectedly poor prognosis. Adequate local control may affect survival. SS is often chemosensitive, and given its poor prognosis, multicenter trials of adjuvant therapy are warranted.

Angiomyofibroblastoma of the vulva. A benign neoplasm distinct from aggressive angiomyxoma.

Aggressive angiomyxoma of pelvic soft parts is a rare lesion with a high risk of recurrence. We report 10 cases of angiomyofibroblastoma, a hitherto uncharacterized benign tumor of the vulva histologically mimicking aggressive angiomyxoma. All patients had a vulval mass, often clinically diagnosed as a Bartholins cyst. There was no recurrence after excision. The tumors were well circumscribed, measuring 0.5–12 cm in maximum dimension. They were characterised by alternating hypercellular and hypocellular edematous zones in which abundant blood vessels (predominantly of the capillary type) were irregularly distributed. Spindled, plump spindled, and oval stromal cells were aggregated around the blood vessels. sometimes forming solid compact foci, or were loosely dispersed in the hypocellular areas. Their nuclei were bland, but rare ones were enlarged and hyperchromatic in four cases. Some cells had abundant eosinophilic hyaline cytoplasm and eccentrically placed nuclei. Mitotic figures were absent or very sparse. Scattered throughout were thin, wavy strands or thick bundles of collagen. Mast cells were readily seen in eight cases. Immunohistochemically, the stromal cells were reactive for vimentin and desmin, but not cytokeratin, muscle-specific actin, a-smooth muscle actin, or S-100 protein. Ultrastructural studies showed well-developed rough endoplasmic reticulum, Golgi apparatus, abundant intermediate filaments, and pinocytotic vesicles in the stromal cells. Angiomyofibroblastoma can be distinguished from aggressive angiomyxoma by its circumscribed borders, much higher cellularity, more numerous blood vessels (which lack prominent hyalinization), frequent presence of plump stromal cells, minimal stromal mucin, and rarity of erythrocyte extravasation.

Expression of bcl-2 oncoprotein in benign and malignant spindle cell tumors of soft tissue, skin, serosal surfaces, and gastrointestinal tract

An immunohistochemical study to determine the pattern of immunoreactivity for bcl-2 oncoprotein was performed in 380 spindle cell tumors of soft tissue, skin, serosal surfaces, and gastrointestinal tract. The cases studied included examples of benign, reactive spindle cell proliferations to benign and malignant spindle cell neoplasms, including nodular fasciitis (10), fibromatosis (5), dermatofibroma (10), dermatofibrosarcoma protuberans (18), Kaposis sarcoma (15), spindle cell lipomatous tumors (24), benign and malignant smooth muscle tumors (35), neural/peripheral nerve sheath neoplasms (53), synovial sarcomas (70) solitary fibrous tumors of serosal surfaces and other sites (56), gastrointestinal stromal tumors (GIST) (47), and malignant undifferentiated fibroblastic spindle cell proliferations of soft tissue (37 cases). The results of bcl-2 staining was additionally correlated with CD34 immunoreactivity. Bcl-2 was uniformly negative in all cases of nodular fasciitis, fibromatosis, and dermatofibroma, as well as in benign and malignant smooth muscle proliferations. Strong positivity for bcl-2 was observed in all cases of spindle cell lipoma, dendritic fibromyxolipoma, Kaposis sarcoma, solitary fibrous tumors, gastrointestinal stromal tumors, and in the spindle cell component of synovial sarcoma. With the exception of the last, there appeared to be a close correlation between the expression of bcl-2 and CD34 in these tumors. Strong bcl-2 positivity also was found, at least focally, in approximately one third of benign and malignant peripheral nerve sheath tumors, particularly in the better-differentiated (Antoni type A) areas. Sarcomas of fibroblastic type, including low-grade myxofibrosarcoma, malignant fibrous histiocytoma, and fibrosarcoma, showed variable expression of bcl-2 in the tumor cells. Our results appear to indicate that bcl-2 may have a wide distribution among benign and malignant spindle cell neoplasms. Strong expression of this marker in some of these conditions, particularly solitary fibrous tumor, gastrointestinal stromal tumors, and synovial sarcoma, may be of aid for differential diagnosis.

Diffusion-weighted magnetic resonance imaging: a potential non-invasive marker of tumour aggressiveness in localized prostate cancer

AIM To evaluate diffusion-weighted magnetic resonance imaging (DW-MRI) as a marker for disease aggressiveness by comparing tumour apparent diffusion coefficients (ADCs) between patients with low- versus higher-risk localized prostate cancer. METHOD Forty-four consecutive patients classified as low- [n = 26, stageT1/T2a, Gleason score < or = 6, prostate-specific antigen (PSA)< 10 (group 1)] or intermediate/high- [n = 18, stage > or = T2b and/or Gleason score > or = 7, and/or PSA > 10 (group 2)] risk, who subsequently were monitored with active surveillance or started neoadjuvant hormone and radiotherapy, respectively, underwent endorectal MRI. T2-weighted (T2W) and DW images (5 b values, 0-800 s/mm(2)) were acquired and isotropic ADC maps generated. Regions of interest (ROIs) on T2W axial images [around whole prostate, central gland (CG), and tumour] were transferred to ADC maps. Tumour, CG, and peripheral zone (PZ = whole prostate minus CG and tumour) ADCs (fast component from b = 0-100 s/mm(2), slow component from b = 100-800 s/mm(2)) were compared. RESULTS T2W-defined tumour volume medians, and quartiles were 1.2 cm(3), 0.7 and 3.3 cm(3) (group 1); and 6 cm(3), 1.3 and 16.5 cm(3) (group 2). There were significant differences in both ADC(fast) (1778 +/- 264 x 10(-6) versus 1583 +/- 283 x 10(-6) mm(2)/s, p = 0.03) and ADC(slow) (1379 +/- 321 x 10(-6) versus 1196 +/- 158 x 10(-6) mm(2)/s, p = 0.001) between groups. Tumour volume (p = 0.002) and ADC(slow) (p = 0.005) were significant differentiators of risk group. CONCLUSION Significant differences in tumour ADCs exist between patients with low-risk, and those with higher-risk localized prostate cancer. DW-MRI merits further study with respect to clinical outcomes.

Nuclear beta-catenin expression distinguishes deep fibromatosis from other benign and malignant fibroblastic and myofibroblastic lesions.

Deep fibromatoses (desmoid tumors) are clonal myofibroblastic proliferations that are prone to aggressive local recurrences but that do not metastasize. They must be distinguished from a host of fibroblastic and myofibroblastic lesions as well as from smooth muscle neoplasms. Virtually all deep fibromatoses have somatic β-catenin or adenomatous polyposis coli (APC) gene mutations leading to intranuclear accumulation of β-catenin. Since low-grade sarcomas in general lack β-catenin and since reactive proliferations would not be expected to have it, we predicted that nuclear β-catenin expression would be detected in deep fibromatoses but absent in other entities in the differential diagnosis. We evaluated the role of β-catenin to help differentiate distinguish deep fibromatoses from congeners. Formalin-fixed, paraffin-embedded sections from 21 lesions from 20 patients with deep fibromatoses were stained with monoclonal β-catenin antibody (Transduction Laboratories) and compared with low-grade fibromyxoid sarcoma (n = 12), leiomyosarcoma (n = 10), various other fibrosarcoma variants (n = 13, including 3 myofibrosarcomas, 3 sclerosing epithelioid fibrosarcomas, 5 low-grade fibrosarcomas, 1 classic fibrosarcoma arising in dermatofibrosarcoma protuberans, 1 inflammatory myxohyaline tumor/myxoinflammatory fibroblastic sarcoma), myofibroma/myofibromatosis (n = 12), nodular fasciitis (n = 11), and scars (n = 9). Nuclear and cytoplasmic staining was assessed. All 21 examples of deep fibromatosis displayed nuclear β-catenin (focal nuclear staining in one case to 90% staining). All other lesions tested (n = 67) lacked nuclear labeling for β-catenin, showing only cytoplasmic accumulation. β-Catenin immunohistochemistry separates deep fibromatosis from entities in the differential diagnosis, a finding that can be exploited for diagnosis. Most fibromatoses have diffuse nuclear staining although occasional examples only focally label.

Diversity of TMPRSS2-ERG fusion transcripts in the human prostate

TMPRSS2-ERG gene fusions have recently been reported to be present in a high proportion of human prostate cancers. In the current study, we show that great diversity exists in the precise structure of TMPRSS2-ERG hybrid transcripts found in human prostates. Fourteen distinct hybrid transcripts are characterized, each containing different combinations of sequences from the TMPRSS2 and ERG genes. The transcripts include two that are predicted to encode a normal full-length ERG protein, six that encode N-terminal truncated ERG proteins and one that encodes a TMPRSS2-ERG fusion protein. Interestingly, distinct patterns of hybrid transcripts were found in samples taken from separate regions of individual cancer-containing prostates, suggesting that TMPRSS2-ERG gene fusions may be arising independently in different regions of a single prostate.