The addition of oral idarubicin to a chlorambucil/dexamethasone combination has a significant impact on time to treatment failure but none on overall survival in patients with low grade non-Hodgkin's lymphoma: Results of the Scotland and Newcastle Lymphoma Group randomized NHL VIII trial.

Two hundred untreated patients with low grade NHL (KIEL), including 155 follicular NHL, were randomized to six courses of treatment with chlorambucil 20 mg m-2 for 3 days and dexamethasone 4 mg bd for 5 days (CD) vs the same regimen plus oral idarubicin 10 mg m-2 for 3 days (CID). Responding patients could be randomized to no further treatment or maintenance treatment for up to 36 months with alpha interferon. Complete remissions/CRu were more frequent in the CID arm (35% vs 24%) but the overall response rate was similar; 87/91 (96%) vs 86/92 (93%). Overall survival (OS) did not differ between the two arms. Time to treatment failure (TTTF) was prolonged in the CID arm, p = 0.03; median time 28 vs 19 months. TTTF for the B-cell follicular group alone was for CID (77 patients) 33 months vs 18 months for CD (78 patients). Interferon conferred no apparent benefit. The Follicular Lymphoma International Prognostic Index (FLIPI) is confirmed as a good predictor of risk groups including a group of 23% with shorter survival. The addition of the oral anthracycline, idarubicin, led to a significant improvement in TTTF with low toxicity. The use of radiotherapy in this sub-group may have contributed to this result. CID is a potential for combination with antibody therapy particularly in older patient groups.

Total registration of non-Hodgkin's lymphoma and Hodgkin's disease in Scotland: effect of deprivation and caseload on outcome.

All cases S16 years of age with a histological diagnosis of non-Hodgkin's lymphoma (NHL) and Hodgkin's disease (HD) presented in Scotland between 1 January 1994 and 31 December 1996 were registered prospectively in the Scotland and Newcastle Lymphoma Group database by a process of total registration. The census population of Scotland in 1996-1997 was 5.1 million. One thousand seven hundred and sixty three patients were registered with NHL and 350 patients with HD. These patients have been followed up for a median of 47 months in the case of NHL and 51 months for HD cases. Actuarial 5-year survival for adult NHL was 35% and for HD, 75%. Outcome for both NHL and HD was particularly poor in the population over 60 years with median survival of 18 months for NHL and 27 months for HD. When analysis of survival was related to degree of material deprivation using the Carstairs score a significantly poorer survival was seen for NHL with increasing deprivation that could not be explained by a different pattern of age or stage at presentation. Deprivation had no impact on incidence or survival in HD. Analysis of impact of caseload of the physician initiating therapy showed no significant difference in 5-year survival.

Observer variability in the Goseki grouping of gastric adenocarcinoma in resection and biopsy specimens.

AIMS: The Goseki grouping of gastric adenocarcinoma has been suggested as a possible prognostic factor. In those centres where it is used, it may be valuable to assess the Goseki grouping of a tumour on the initial diagnostic biopsy as well as on the resection specimen since it may in theory influence management. We examined the robustness of Goseki grouping of gastric adenocarcinoma in representative sections from resection and biopsy specimens in order to assess the consistency of agreement among a group of pathologists. METHODS: A single representative block from 100 gastric resection specimens was studied using a haematoxylin and eosin and mucin (alcian blue/periodic acid-Schiff) stain. These were circulated in batches to members of a group of 12 pathologists who each completed a simple proforma confirming the presence of carcinoma and assigning a Goseki group. In a second circulation the diagnostic biopsy specimen taken prior to resection was examined in the same way. This allowed comparison of the Goseki group of the biopsy and resection specimens. RESULTS: In both studies kappa statistics showed good agreement on tubular differentiation of the carcinoma, but only moderate agreement for the intracellular mucin production, resulting in moderate agreement for the final Goseki group. Correlation between the Goseki group assigned on the biopsy and resected specimens was seen in 62% of the cases. However, the reproducibility was low (kappa 0.375). CONCLUSIONS: The Goseki grouping of resected gastric adenocarcinoma is reproducible and can be used in prognostication. Goseki grouping of biopsy specimens is of limited value in predicting the Goseki group assigned to the resected carcinoma.

Nuclear thymidylate synthase expression, p53 expression and 5FU response in colorectal carcinoma.

Thymidylate synthase (TS) is a key enzyme in DNA synthesis and is inhibited by metabolites of the chemotherapeutic agent 5-fluorouracil (5FU). Nuclear expression of TS in human tissue in vivo has not been characterised and its clinicopathological correlates in malignancy are unknown. 52 cases of primary colorectal carcinoma (CRC) and 24 cases of matched metastatic carcinoma were studied immunohistochemically using the monoclonal antibody TS106. The degree of nuclear TS immunostaining correlated closely with levels of TS mRNA expression amongst 10 CRCs studied. Strong nuclear immunostaining was seen in normal basal crypt colonocytes and germinal centre cells, and in a varying proportion of adenocarcinoma cells. Amongst the primary carcinomas, higher TS nuclear expression was associated with prominent extracellular mucin production and right-sided location. Higher TS nuclear expression also showed a significant association with poorer response to protracted venous infusional 5FU therapy. There was no clear association between TS nuclear expression and Ki67 or p53 expression assessed immunohistochemically. There was a strong positive correlation between TS nuclear expression in primary and metastatic CRC but the latter generally showed higher expression than matched primary tumour tissue. These findings confirm the nuclear expression of TS protein in human cells in vivo and provide new insight into how such expression may relate to the behaviour of CRCs.

Consistency of histopathological reporting of laryngeal dysplasia. The Scottish Pathology Consistency Group.

AIMS: Clinical management of premalignant and malignant lesions of the larynx is dependent on histopathological evaluation. The Scottish Pathology Consistency Group assessed interobserver variation in the evaluation of laryngeal dysplasia. METHODS AND RESULTS: One hundred laryngeal biopsies ranging from normal to invasive carcinoma were assessed. The overall Kappa result of 0.32 was disappointing. However, agreement on those categories which dictate significantly different management was more favourable. The Kappa figure for mild dysplasia versus severe dysplasia/CIS was 0.7, the Kappa figure for mild dysplasia versus severe dysplasia/CIS and invasive carcinoma was 0.77. The Kappa figure for mild and moderate dysplasia versus severe dysplasia/ CIS and invasive carcinoma was 0.57. An attempt to use a two grade system gave a Kappa figure of 0.52. CONCLUSIONS: Our group had a satisfactory agreement on the distinction of mild from severe dysplasia and on microinvasive carcinoma without any discussion as to histopathological criteria to be used. Clinical management--review endoscopy, repeat cord stripping, radiotherapy and laryngectomy--is in general dependent on histological assessment. Thus the agreement on categories which underpin clinical management is reassuring. However, assessment of moderate dysplasia remains problematic. An attempt to utilize a two grade system--low grade from high grade dysplasia/CIS--may have merit. The implications of the terminology used must be agreed among pathologists and clinicians working closely within clinicopathological cancer groups.

In vitro analysis of coronary atheromatous lesions by intravascular ultrasound; reproducibility and histological correlation of lesion morphology.

AIM: To determine the reproducibility and histological correlation of qualitative intravascular ultrasound imaging of atheromatous coronary arteries using the recently proposed European Society of Cardiology classification of plaque composition in conditions approximating the clinical setting. METHODS: Atheromatous lesions (n=21), identified from 30 post-mortem human coronary arteries, were imaged using intravascular ultrasound in a pulsatile flow system which simulates coronary flow. Fifty sites (21 x minimum lumen area and 29 x distal reference sites) were selected independently by two observers from continuous video recordings. Atheromatous plaque was classified as echodense, echolucent, heterogeneous or calcified by each observer and by one observer on separate occasions. Arterial specimens were histologically sectioned at these sites and similarly analysed by a third observer blinded to the intravascular ultrasound appearances. RESULTS: Overall inter- and intra-observer reproducibility for plaque-type (Kappa 0.87[0.80-0.94] and 0.89[0. 85-0.93 respectively]) and focal calcification (0.78[0.74-0.82] and 0.88[0.84-0.92]) was high. Differences in site selection significantly influenced reproducibility particularly at reference sites. Agreement for overall plaque type between intravascular ultrasound and histology occurred in 89% of sites (Kappa 0.73[0.69-0. 77]). Specificity and positive predictive values for individual plaque types were greater than 90%. CONCLUSION: Using modern intravascular ultrasound technology in an in vitro system which approximates the clinical setting the proposed ESC classification of plaque composition by intravascular ultrasound is reproducible and correlates well with histology. It should therefore perform reliably in diagnostic intravascular ultrasound examinations and in the guidance of percutaneous coronary interventions.

Primary non-Hodgkins lymphoma of muscle.

A retrospective analysis was made of all patients with primary muscle non-Hodgkin's lymphomas registered with the Scotland and Newcastle Lymphoma Group over a 15-year period. Only eight patients were identified. The median age was 69 years (range 27-93). Five patients were male and six lymphomas were of high grade histology. The glutei and upper arm muscles were the main sites of origin, with the additional involvement of adjacent bone in four patients; only three had lymph node involvement at presentation. Most patients (6/8) received both chemotherapy and radiotherapy. The median survival was 33 months. The conclusion is that this is a small group of patients whose outlook is not as poor as has been suggested in previous reports.

Nitric oxide and gall-bladder motor function.

BACKGROUND: The L-arginine: nitric oxide (NO) pathway has been shown to be important in the regulation of intestinal motility and NO may be the mediator for nonadrenergic noncholinergic (NANC) neurotransmission. AIM: To determine the role of the L-arginine: NO pathway in gall-bladder motor function. METHODS: Strips of fresh bovine and human gall-bladders were stimulated with cholecystokinin (CCK). The effects of glyceryl trinitrate (GTN), sodium nitroprusside and Kreb's solution upon CCK-stimulated muscle contraction were examined. The effect of the NO synthase inhibitor, L-NG-monomethyl-arginine (L-NMMA) upon basal muscle tone was also examined. Ten human gall-bladders were immunohistochemically stained for nitric oxide synthase (NOS) and product 9.5 to identify neurones. Postprandial gall-bladder emptying was measured on separate occasions in six healthy volunteers during systemic intravenous infusion of normal saline; glyceryl trinitrate; sodium nitroprusside (SNP), hydralazine and L-NMMA. RESULTS: In the in vitro study, GTN and SNP significantly reduced the tension of CCK-stimulated muscle contraction whilst Kreb's solution had no effect. L-NMMA increased tonic and phasic muscle contractions. Immunohistochemical staining for NOS was consistently absent in human gall-bladders. In the in vivo study, both GTN and SNP caused significant impairment of gall-bladder emptying; the ejection fraction was only 50% at the end of the study period involving these infusates, this contrasted with ejection fractions in excess of 80% during infusions with hydralazine, saline and L-NMMA. CONCLUSION: Pharmacological doses of NO donors impair postprandial gall-bladder emptying in vivo and relax gall-bladder smooth muscle in vitro. However, negative immunohistochemical staining suggest NOS is unlikely to be the neurotransmitter for NANC innervation regulating gall-bladder motility.

CHOP-based chemotherapy is as effective as alternating PEEC/CHOP chemotherapy in a randomised trial in high-grade non-Hodgkin's lymphoma. Scotland and Newcastle Lymphoma Group.

The aim of this study was to test whether survival for patients with high-grade non-Hodgkin's lymphoma (NHL) can be improved with a non-cross-resistant regimen as compared to a CHOP-based regimen. This is a multicentre study comprising 325 adult patients, median age 58 years, with high-grade non-Hodgkin's lymphoma: patients of any age and performance status were eligible provided they were able to receive the drugs in the regimens. Patients were randomised to either B-CHOP-M (bleomycin, cyclophosphamide, doxorubicin, vincristine, prednisolone and methotrexate) or PEEC-M (methylprednisolone, vindesine, etoposide, chlorambucil and methotrexate) alternating with B-CHOP-M. At a median follow-up of 9 years, there was no significant difference in overall survival or disease-free survival between the two arms. Toxicities for the two regimens were equivalent. This study confirms that for relatively unselected patients with high-grade non-Hodgkin's lymphoma, an alternating multidrug regimen does not improve upon the results obtained with B-CHOP-M.

Observer variability in the histopathological reporting of needle biopsy specimens of the prostate.

The Scottish Pathology Consistency Group has in previous studies examined the consistency of histopathological reporting of biopsies from the cervix, bladder, bronchus, and rectum. In the current study, consisting of 100 needle biopsy specimens of the prostate, a single hematoxylin-eosin (H&E) slide from each case was circulated in batches of 10 to the 12 pathologists, who filled in a simple proforma. This had two sections: a diagnostic category (benign; suspicious or malignant) along with a standard Gleason score for those regarded as malignant. The majority diagnosis of the 100 cases was benign, 53; suspicious, 1; and malignant, 46. The Kappa value for benign cases versus others was 0.86 and for malignant cases versus others was 0.91. Analysis of the data on Gleason scores showed a value of 0.54 when cases were divided into two categories (2 to 6 v 7 to 10) and 0.41 when three categories were used (2 to 4; 5 to 6; 7 to 10). Although not initially part of the design of the study, the majority diagnosis was compared with the original reported diagnosis. In a small subset, examination of further levels, basal cell antibody staining, along with further clinical information, was obtained. With this added information, it appears that there were probably 52 benign and 48 malignant cases. Of the 48 malignant cases, the group majority diagnosis was malignant, 46; suspicious, 1; and benign, 1. The original reported diagnosis was 56 benign, 1 suspicious, and 43 malignant. The group therefore appeared to perform better than the original reporting pathologists. When compared with the results of our previous studies, this study has shown that the diagnosis of carcinoma of the prostate on a needle biopsy is robust.

Experimental studies of injection therapy for ulcer haemorrhage in rabbits.

BACKGROUND: Endoscopic injection therapy is a well established method of controlling peptic ulcer haemorrhage but the optimum injection solution and the mechanism involved in inducing haemostasis are unknown. METHODS: The efficacy and effects on tissue of various therapeutic agents used in the control of gastric mucosal haemorrhage were studied in ten rabbits. Thirty-eight bleeding mucosal ulcers (blood loss above 1.5 ml/min) created at gastrotomy were studied. Adrenaline (1:100,000), thrombin, fibrin (thrombin plus fibrinogen), 5 per cent ethanolamine and 50 per cent dextrose were injected; a fibrin suspension was also sprayed around bleeding ulcers. RESULTS: Sclerosants were found to be least effective in the control of bleeding and were associated with significant tissue necrosis. Although all the other solutions significantly decreased blood loss within 30 min of injection (median blood loss 0.25 ml/min), only an injected mixture of adrenaline plus thrombin and sprayed fibrin achieved complete haemostasis within 2 min of treatment and with no recurrence of bleeding. Neither agent caused significant tissue damage. Histological examination showed that no solution caused arterial thrombosis when injected next to a major ear artery. CONCLUSION: Sclerosants caused extensive tissue necrosis and were least effective in the control of ulcer haemorrhage. A combination of dilute adrenaline and human thrombin may represent optimal haemostatic therapy for peptic ulcer haemorrhage.

Estrogen secretion from a malignant sex cord stromal tumor in a patient with complete androgen insensitivity.

We report on a 68-year-old patient with complete androgen insensitivity syndrome (testicular feminization syndrome) in whom an estrogen-secreting malignant sex cord stromal tumor developed in an intraabdominal testis. We believe this to be the first such case to document estrogen secretion by the tumor.

Analysis of retinoblastoma gene expression in human prostate tissue.

The retinoblastoma (RB) gene has been reported to be deleted in a number of human cancers including urologic tumors. In the present study, we used polymerase chain reaction (PCR) employing total RNA extracted from snap-frozen tumor specimens of ten benign prostatic hyperplasia and nine cancer specimens to test for the presence of a short sized mRNA transcript to screen for point mutations at the exon-intron boundaries between exons 13 and 23. None of the tissue entered in the study showed any evidence of an aberrant short sized mRNA. In addition, we used DNA-PCR to investigate deletional changes within exons 13 and 17 in an additional 5 benign lesions and 18 adenocarcinomas of the prostate but failed to demonstrate any deletions within exons 13 and 17 at the DNA levels in these cancer specimens. Furthermore, we examined the immunostaining patterns for the RB protein in the benign and malignant glands but found no significant difference between the two groups. We therefore concluded that, in contrast to other human tumors, the RB gene is not commonly altered in cancer of the prostate.

Expression of the extracellular matrix protein tenascin in malignant and benign ovarian tumours.

The extracellular matrix protein tenascin (TN) is overexpressed in a number of solid tumours. Thi however, is the first study to examine TN expression in ovarian tumours. TN protein was examined in froze sections of 50 human ovarian tumours by immunohistochemistry. Malignant and borderline tumours showed significantly greater incidence and intensity of stromal staining than benign tumours (P < 0.0001 and P = 0.038 respectively). Seven omental metastases were also examined and showed a strikingly similar protein distribution to their primary tumour counterparts. The expression pattern of different RNA isoforms, created by alternative splicing of the primary transcript, was identified using reverse transcription-polymerase chain reactions (RT-PCR). The smallest TN RNA splice variant (284 bp) was found in all tumours examined, while the appearance of larger molecular weight transcripts (approximately 490 and 556 bp), as major forms, was predominantly limited to malignant tumours, with 9/12 malignant tumours showing this pattern compared with 1/6 benign tumours. These data suggest that malignant ovarian tumours have increased expression of TN compared with benign tumours and this may be associated with induction of specific isoforms.

Ductal (endometrioid) adenocarcinoma of the prostate: a clinicopathological study of 16 cases.

Sixteen cases of ductal (endometrioid) carcinoma of the prostate are presented. The tumour presents in elderly men (age range 65-87 years) with haematuria or obstructive symptoms. Serum prostate specific antigen may be normal or raised. On cytoscopy, there is often an exophytic lesion in the region of the verumontanum. Histologically, two variants are recognized: papillary and cribriform, of which there were eight cases each. Eight cases consisted of pure ductal carcinoma and seven were mixed, containing a variable proportion of micro-acinar carcinoma. The associated micro-acinar carcinoma had a Gleason score of at least 5. One case of carcinosarcoma with a ductal epithelial component was also included. All cases displayed positive immunohistochemical staining for prostate specific antigen and prostatic acid phosphatase and but were negative for the basal cell marker MA903. The tumour responds well to orthodox micro-acinar carcinoma therapy and appears notably sensitive to hormonal manipulation. Follow-up of the mixed group is restricted to a maximum of 3 years. Of the eight pure cases, five patients are still alive with survival periods of 11, 8, 7, 3 and 1 years. Three patients died of intercurrent disease of which one patient survived 12 years, having received no treatment. This tumour, therefore, can be regarded as having a good prognosis.

The prognostic value of epidermal growth factor receptor mRNA expression in primary ovarian cancer.

The expression of mRNA for the epidermal growth factor (EGF) receptor, EGF and transforming growth factor alpha (TGF-alpha) was determined in 76 malignant, six borderline and 15 benign primary ovarian tumours using the reverse transcriptase-polymerase chain reaction and related to clinical and pathological parameters. Of the malignant tumours, 70% (53/76) expressed EGF receptor mRNA, 31% (23/75) expressed EGF mRNA and 35% (26/75) expressed TGF-alpha mRNA. For the borderline tumours, four of six (67%) expressed EGF receptor mRNA, 1/6 (17%) expressed TGF-alpha mRNA and none expressed EGF mRNA. Finally, 33% (5/15) of the benign tumours expressed EGF receptor mRNA, whereas 40% (6/15) expressed EGF mRNA and 7% (1/15) expressed TGF-alpha mRNA. The presence of the EGF receptor in malignant tumours was associated with that of TGF-alpha (P = 0.0015) but not with EGF (P = 1.00), whereas there was no relationship between the presence of EGF and TGF-alpha (P = 1.00). EGF receptor mRNA expression was significantly and positively associated with serous histology (P = 0.006) but not with stage or grade. Neither EGF nor TGF-alpha showed any link with histological subtype or stage. The survival of patients with malignant tumours possessing EGF receptor mRNA was significantly reduced compared with that of patients whose tumours were negative (P = 0.030 for all malignant tumours; P = 0.007 for malignant epithelial tumours only). In contrast, neither the expression of TGF-alpha nor EGF was related to survival. These data suggest that the presence of EGF receptor mRNA is associated with poor prognosis in primary ovarian cancer.