Long-term follow-up of cervical disease in women screened by cytology and HPV testing: results from the HART study.

BACKGROUND: Several studies have shown that testing for high-risk human papillomavirus (HPV) types results in an improved sensitivity for CIN2+, compared with cytology, although with a somewhat lower specificity. METHODS: We obtained follow-up results, with at least one smear after participation in the HART study, which compared HPV testing (HC-II) with cytology as a primary screening modality. RESULTS: With a median follow-up of 6 years, 42 additional cases of CIN2+ were identified; women who were HPV positive at baseline were more likely to develop CIN2+ than those who were HPV negative (hazard ratio (HR) 17.2; 95% confidence interval (CI) (9.3-31.6)) and the risk increased with increasing viral load. Compared with HPV-negative women (relative light unit (RLU) <1), the HR (95% CI) was 5.4 (1.6, 18.2) for 1-10 RLU and 25.5 (13.6, 47.9) for RLU > or = 10. Positive cytology (borderline or worse compared with negative) was also predictive of developing CIN2, although to a lesser extent (HR 8.7; 95% CI (4.5-17.1)). Only one case of CIN3 and three cases of CIN2 were found in women who showed a positive cytology result but were HPV negative at baseline. CONCLUSION: After 5 years of follow-up, CIN2+ occurred in 0.23% of women who were HPV negative at baseline compared with 0.48% of women who showed a negative cytology result, indicating a much longer low-risk interval for CIN2+ after HPV testing.

Cytoplasmic PML promotes TGF-ß-associated epithelial-mesenchymal transition and invasion in prostate cancer.

Epithelial-mesenchymal transition (EMT) is a key event that is involved in the invasion and dissemination of cancer cells. Although typically considered as having tumour-suppressive properties, transforming growth factor (TGF)-ß signalling is altered during cancer and has been associated with the invasion of cancer cells and metastasis. In this study, we report a previously unknown role for the cytoplasmic promyelocytic leukaemia (cPML) tumour suppressor in TGF-ß signalling-induced regulation of prostate cancer-associated EMT and invasion. We demonstrate that cPML promotes a mesenchymal phenotype and increases the invasiveness of prostate cancer cells. This event is associated with activation of TGF-ß canonical signalling pathway through the induction of Sma and Mad related family 2 and 3 (SMAD2 and SMAD3) phosphorylation. Furthermore, the cytoplasmic localization of promyelocytic leukaemia (PML) is mediated by its nuclear export in a chromosomal maintenance 1 (CRM1)-dependent manner. This was clinically tested in prostate cancer tissue and shown that cytoplasmic PML and CRM1 co-expression correlates with reduced disease-specific survival. In summary, we provide evidence of dysfunctional TGF-ß signalling occurring at an early stage in prostate cancer. We show that this disease pathway is mediated by cPML and CRM1 and results in a more aggressive cancer cell phenotype. We propose that the targeting of this pathway could be therapeutically exploited for clinical benefit.

Management of women who test positive for high-risk types of human papillomavirus: the HART study.

BACKGROUND: Certain types of human papillomavirus (HPV) are the primary cause of almost all cervical cancers. HPV testing of cervical smears is more sensitive but less specific than cytology for detecting high-grade cervical intraepithelial neoplasia (CIN2+). HPV testing as a primary screening approach requires efficient management of HPV-positive women with negative or borderline cytology. We aimed to compare the detection rate and positive predictive values of HPV assay with cytology and to determine the best management strategy for HPV-positive women. METHODS: We did a multicentre screening study of 11085 women aged 30-60 years. Women with borderline cytology and women positive for high-risk HPV with negative cytology were randomised to immediate colposcopy or to surveillance by repeat HPV testing, cytology, and colposcopy at 12 months. FINDINGS: HPV testing was more sensitive than borderline or worse cytology (97.1% vs 76.6%, p=0.002) but less specific (93.3% vs 95.8%, p<0.0001) for detecting CIN2+. Of 825 randomised women, surveillance at 12 months was as effective as immediate colposcopy. In women positive for HPV at baseline, who had surveillance, 73 (45%) of 164 women with negative cytology and eight (35%) of 23 women with borderline cytology were HPV negative at 6-12 months. No CIN2+ was found in these women, nor in women with an initial negative HPV test with borderline (n=211) or mild (32) cytology. INTERPRETATION: HPV testing could be used for primary screening in women older than 30 years, with cytology used to triage HPV-positive women. HPV-positive women with normal or borderline cytology (about 6% of screened women) could be managed by repeat testing after 12 months. This approach could potentially improve detection rates of CIN2+ without increasing the colposcopy referral rate.

Non-Hodgkin's lymphoma in elderly patients: a phase II study of MCOP chemotherapy in patients aged 70 years or over with intermediate- or high-grade histology.

During the period 1 January 1988 to 31 July 1991, 74 patients were seen with intermediate- or high-grade non-Hodgkin's lymphoma who were aged 70 years or over. Of these 74 patients, 20 were treated with radiotherapy alone, and 46 were judged as suitable for treatment with the chemotherapy regime MCOP (mitoxantrone, cyclophosphamide, vincristine and prednisolone). Involved field radiotherapy (35-40 Gy in 20 fractions over 4 weeks) was given to 14 of the 21 patients with stage IA and IIA disease, and 6 of the 25 patients with stage III and IV disease after completion of chemotherapy. The complete response rate was 63% at the completion of all treatment (6 months), and 39% at 12 months. There were no treatment-related deaths, and the 3-year cause-specific survival was 26% (overall survival 21%). For patients aged 70-75 years, the 3-year cause-specific survival was 34% in comparison to 17% for those patients aged 76-93 years. The chemotherapy was well tolerated by those patients aged 70 years and over, 70% of the patients did not vomit and no patients had significant vincristine neuropathy. There were only four infections associated with neutropenia. All patients completing six cycles had moderate, patchy alopecia. This MCOP regime is suitable for patients aged 70 years and over with intermediate- and high-grade non-Hodgkin's lymphoma. The survival of patients is comparable to that obtained with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) with less apparent toxicity.

Frequency of cervical intraepithelial neoplasia following large loop excision of the transformation zone.

AIM: To determine the frequency of cervical intraepithelial neoplasia (CIN) following large loop excision of the transformation zone of the cervix (LLETZ) according to grade and completeness of excision of CIN. METHODS: A retrospective study of 669 patients who had LLETZ biopsies showing CIN 1, 2, or 3. The patients were subdivided according to the grade and completeness of excision of CIN. The follow up period was 1.5 to 3.5 years. Risk of persistent/recurrent CIN was assessed by the frequency of histological diagnosis of CIN during the follow up period. RESULTS: Frequency of persistent/recurrent CIN increased with the grade of CIN reported: 6.7% of patients with CIN 1, 13.4% with CIN 2, and 21.7% with CIN 3 developed persistence or recurrence. The frequency of CIN persistence/recurrence was significantly lower where LLETZ showed complete excision of CIN (8.4%) than where it was incomplete (31.3%) (p < 0.0001) or equivocal (27.8%) (p < 0.0001). CONCLUSIONS: Patients with incomplete or equivocal excision of all grades of CIN merit careful, preferably colposcopic, follow up. Patients with completely excised high grade CIN require careful cervical cytologic surveillance.

Fat macroglobule formation from chylomicrons and non-traumatic fat embolism.

Chylomicrons show calcium-dependent agglutination by C-reactive protein (CRP). This has been suggested as a mechanism by which fat embolism may occur in the absence of trauma. It may also play a role in the pathogenesis of acute pancreatitis in patients with types I and V hyperlipidaemia.

Comparison of fat agglutination slide test and latex test for C-reactive protein.

A slide test for detecting elevated levels of serum CRP using Intralipid and calcium chloride is described. The test obtains results similar to those of a latex agglutination test with which it was compared. The test is extremely quick and easy to perform. It may be of use as a cheap alternative to latex agglutination as a rapid screening or bedside test for elevated levels of CRP.

The pathogenesis of fat embolism.

Fat embolism is a common autopsy finding in patients with or without a history of trauma. There are two basic mechanisms causing fat to embolize. Depot-derived fat embolism arises by disruption of depot fat, usually as a result of trauma, allowing direct entry into the bloodstream. Plasma-derived fat embolism is caused by agglutination of endogenous or infused exogenous fat such as Intralipid, with consequent embolism. Chylomicrons and Intralipid liposomes are known to undergo calcium-dependent agglutination by C-reactive protein (CRP), and this may play a role in vivo in this type of fat embolism.

Pathogenesis of non-traumatic fat embolism.

Like the liposomes of certain intravenous fat emulsions associated with embolic effects in acutely ill patients, chylomicrons and very low density lipoproteins (VLDL) show calcium-dependent agglutination by C-reactive protein (CRP). It is suggested that non-traumatic fat embolism may be caused by agglutination of chylomicrons and VLDL by high levels of plasma CRP. This mechanism may also cause acute pancreatitis in patients with types I, IV, and V hyperlipidaemia, and avascular necrosis of bone in patients with corticosteroid-induced hyperlipidaemia.

Intralipid microemboli.

A baby girl died after receiving intravenous Intralipid. At necropsy a pulmonary Intralipid microembolus, unrelated to the cause of death, was found. Serum taken immediately before infusion agglutinated Intralipid. C reactive protein concentration was raised. This supports the theory that C reactive protein may agglutinate Intralipid in vivo, causing embolisation.

Pneumatosis coli: an uncommon but treatable cause of faecal incontinence.

Pneumatosis intestinalis is defined as the presence of gas within the bowel wall. Small bowel pneumatosis is less commonly reported and more severe than colonic disease in adults. Pneumatosis coli is characterised by multiple collections of encysted gas occurring within the sub-mucosa and subserosa of the colon and rectum. It is an uncommon condition which typically presents in late middle age and has been associated with a number of gastrointestinal (e.g. pyloric stenosis, sigmoid volvulus and ischaemic bowel) and non-gastrointestinal (e.g. chronic obstructive pulmonary disease, depression and multiple sclerosis) diseases. Some cases, however, are idiopathic or primary. Symptoms can include diarrhoea, constipation, mucus per rectum, bleeding, flatus, abdominal pain and, rarely, faecal incontinence. We report on two patients, one of whom presented with faecal incontinence, the other who had troublesome lower gastrointestinal symptoms including faecal incontinence. Both responded well to continuous oxygen therapy.

Oral contraceptive use and histopathology of cancerous breasts in young women. Members of the U.K. National Case-Control Study Group.

A retrospective histopathological study of 300 women under 36 years of age was carried out to determine whether breast cancers occurring in oral contraceptive users showed any differences in pathological features compared with non-users. The patients belong to an age group in which an increased risk of cancer development has been reported following oral contraceptive usage. The incidence of non-neoplastic conditions in the residual breast was also studied in the two groups. There was little difference between breast cancers arising in pill users and non-users but in the residual non-neoplastic breast a decreased incidence of cysts and blunt duct adenosis was found in current users of the contraceptive pill. In contrast, lactational foci were found only in the breasts of pill users. The incidence of intraductal hyperplasia was not significantly different in the two groups.

Agglutination of intralipid by sera of acutely ill patients.

The serum of over half of a group of acutely ill patients agglutinated "Intralipid' a fat emulsion based on soya bean oil designed for intravenous infusion. This reaction is probably precipitated by C-reactive protein in the presence of calcium ions. Post-mortem examinations of patients who had received intralipid showed evidence of microembolism which could have been caused by agglutination of intralipid. If this is the case then intralipid should perhaps not be given to these acutely ill patients.