The histone demethylase KDM4B regulates peritoneal seeding of ovarian cancer.

Epithelial ovarian cancer (EOC) has poor prognosis and rapid recurrence because of widespread dissemination of peritoneal metastases at diagnosis. Multiple pathways contribute to the aggressiveness of ovarian cancer, including hypoxic signaling mechanisms. In this study, we have determined that the hypoxia-inducible histone demethylase KDM4B is expressed in ∼60% of EOC tumors assayed, including primary and matched metastatic tumors. Expression of KDM4B in tumors is positively correlated with expression of the tumor hypoxia marker CA-IX, and is robustly induced in EOC cell lines exposed to hypoxia. KDM4B regulates expression of metastatic genes and pathways, and loss of KDM4B increases H3K9 trimethylation at the promoters of target genes like LOXL2, LCN2 and PDGFB. Suppressing KDM4B inhibits ovarian cancer cell invasion, migration and spheroid formation in vitro. KDM4B also regulates seeding and growth of peritoneal tumors in vivo, where its expression corresponds to hypoxic regions. This is the first demonstration that a Jumonji-domain histone demethylase regulates cellular processes required for peritoneal dissemination of cancer cells, one of the predominant factors affecting prognosis of EOC. The pathways regulated by KDM4B may present novel opportunities to develop combinatorial therapies to improve existing therapies for EOC patients.

Plasma lipid-associated sialic acid and serum CA 125 as indicators of disease status with advanced ovarian cancer.

Levels of plasma lipid-associated sialic acid and serum cancer antigen 125 (CA 125) were measured in 49 consecutive patients with advanced ovarian cancer (International Federation of Gynecology and Obstetrics stages III or IV) and in 43 women with benign gynecologic diseases who served as controls. Levels were evaluated in 22 previously untreated patients before initial debulking surgery, in 11 with negative second-look operation, and in 16 with persistent or progressive disease confirmed by second-look operation or reexploration. Plasma lipid-associated sialic acid values had a sensitivity of 100% in previously untreated patients, a specificity of 73% in those with negative second-look, and a sensitivity of 87% in those with positive second-look, or persistent disease. CA 125 values were 77, 100, and 75%, respectively. By combining both markers, there were no false-negative results in previously untreated patients or false-positive results in those who were disease-free. Only one of 16 patients with persistent disease had false-negative results for both markers and progressive disease on reexploration. The predictive values of a positive assay with plasma lipid-associated sialic acid, CA 125, and both markers combined were 92.3, 100, and 100%, respectively. The predictive values of a negative assay were 80, 55, and 88.9%, respectively. The combined use of plasma lipid-associated sialic acid and CA 125 enhanced the individual reliabilities of these tests in patients with advanced ovarian carcinoma.

The value of exploratory laparotomy in patients with endometrial carcinoma according to the new International Federation of Gynecology and Obstetrics staging.

OBJECTIVE: We conducted a retrospective review of 169 consecutive patients diagnosed with endometrial carcinoma to evaluate the advantage of exploratory laparotomy according to the new International Federation of Gynecology and Obstetrics (FIGO) classification as compared with clinical staging. METHODS: All 169 patients were admitted to the Department of Gynecologic Oncology from August 1980 through June 1988 and underwent exploratory laparotomy, which included total abdominal hysterectomy, bilateral salpingo-oophorectomy, and peritoneal washings. We performed complete lymph node dissection of the pelvic and the para-aortic areas on 87 patients with clinical stages I and II. Eighteen more patients were upgraded to stage III or IV during exploratory laparotomy with lymph node biopsy. Forty-nine patients did not have lymph node dissection because of age and medical contraindications. In 15 patients with clinical stage III or IV, lymph node dissection was performed as part of debulking surgery. Clinical staging showed 135 patients (80%) with stage I, 19 (11%) with stage II, three (2%) with stage III, and 12 (7%) with stage IV carcinoma. RESULTS: Surgical restaging according to the new FIGO classification resulted in 117 patients (69%) with stage I, seven (4%) with stage II, 23 (14%) with stage III, and 22 (13%) with stage IV carcinoma. Thirty patients (19%) of 154 with clinical stage I or II had extrauterine spread. Thirty-three of 169 patients (19.5%) had their clinical staging upgraded and six (3.5%) were downgraded. The 5-year actuarial survival rates for clinical stages I, II, and IV were 83, 64, and 8%, respectively. The actuarial survival rates for surgical stages I, II, III, and IV were 89, 100, 58, and 24%, respectively. Cases surgically staged as I with high-risk variables (eg, poor differentiation, unfavorable histologic types, and deep myometrial invasion) or stage II received 5000 cGy to the whole pelvis using a box technique. Patients with surgical stage III or IV received adjuvant intravenous chemotherapy (eg, doxorubicin, hydrochloride, Cytoxan, and cisplatin) consecutively for ten to 12 courses. Megestrol acetate was added for 2 years. CONCLUSIONS: Surgical staging after exploratory laparotomy defined the true extent of disease and identified 20% of the cases that may escape effective treatment.

Passive euthanasia in dementia: killing ... or letting die?

A sample of carers was asked to complete a self-administered questionnaire designed to collect information about carers' characteristics and obtain their views on passive euthanasia. Each carer was given an information sheet about the study, which included a detailed and clear account for the different types of euthanasia. The study showed a strong support for passive euthanasia from the non-professional carers of dementia patients. The strongest support was for the idea of a 'Living Will'. Having previous experience in looking after other people with dementia would appear to influence carers' perception of passive euthanasia. The subject of passive euthanasia and its ramifications for sufferers, carers and professionals warrants further exploration.

Autopsy in elderly psychiatric inpatients: a retrospective review of autopsy findings of deceased elderly psychiatric inpatients in north Cheshire 1980-1996.

In this 17-year review of death certificates of elderly inpatients of a large psychiatric hospital in North Cheshire, the frequency, trend and value of performing autopsies were examined. Details of death certificates were compared with certificates issued after post-mortem examination to see whether an autopsy yielded any additional or relevant information about conditions that are not directly related to death but might well be of importance to public health. The rate of post-mortem examination, at 9.5% of total hospital deaths, did not show any significant trend over most of the review period. The vast majority of autopsies examined had been requested by the coroner and not by the clinicians. The review showed that an autopsy may be of some value in providing more information regarding any underlying causes of death in elderly psychiatric patients, but has no value in ensuring higher rate of the recording of conditions such as dementia, in particular Alzheimer's disease. Selective hospital autopsy in elderly psychiatric patients to verify, neuropathologically, the clinical diagnosis of Alzheimer's disease, will improve our diagnostic accuracy and provide valid statistics to be used in estimating prevalence, trends, risk factors and for use in all aspects of future research into Alzheimer's disease.

Elderly suicide and attempted suicide: one syndrome.

In this study we explore whether elderly suicide victims who had a previous history of attempted suicide differ from those with no similar history. A group of the elderly, who ended their lives with fatal self-harm (FSH) and had a history of deliberate self-harm (DSH) was compared to a matching group of the elderly who also ended their lives with FSH, but who were not known to have had any history of DSH. The comparison was in respect of epidemiological, social, psychological characteristics, service input and methods of suicide. The elderly, with a history of DSH, were more likely to have been known to the mental health services than the elderly who did not have such a history (P<.05). The two groups used similar methods in their final FSH act. The elderly victims of FSH with or without a previous history of DSH share the same characteristics. The two groups appear to be part of one syndrome. Deliberate self-harm in the elderly should be taken seriously as an unsuccessful suicide rather than a manipulative act or a cry for help and attention.

History of deliberate self harm may predict methods of fatal self harm in the elderly.

In this study we examined the association between methods of Deliberate Self Harm (DSH) by the elderly and their subsequent methods of Fatal Self Harm (FSH). Data was collected from the files of inquests into suicide by the elderly in Birmingham and Cheshire Coroner's Courts. All the subjects were above the age of 60, had history of deliberate self harm before the final act of fatal self harm and attracted either suicide or open verdict returned by the Coroners over a period of four years 1995-1998. We compared the methods of Deliberate Self Harm (DSH) to the methods of Fatal Self Harm (FSH) used by all the included elderly. 18 per cent of elderly victims of FSH had a previous history of DSH and in 35 per cent of the sample, the last known attempt of DSH occurred more than one year prior to the FSH. The majority of the methods that had been used in elderly DSH were used again in their final act of FSH. Nearly two thirds of all the elderly who died of an overdose had attempted suicide earlier by an overdose and one in five of those who died by hanging or drowning used the same method in an unsuccessful attempt of FSH within 12 months. A detailed history of DSH can improve the quality of risk assessment of self harm in the elderly. As more than one in three elderly victims of FSH attempted DSH more than a year prior to the final act, it is important when assessing an elderly DSH attempt that we obtain any previous case notes and question informants about the distant as well as the recent past.

Detention of elderly psychiatric inpatients under section 5(2) of the Mental Health Act 1983.

Emergency detention of elderly psychiatric inpatients appears to have attracted very little or no attention in published studies. In this retrospective review, all applications of sections 5(2) and 5(4) of the Mental Health Act 1983, detaining elderly inpatients in North Cheshire between 1985 and 1997 were reviewed. Forty-three percent of elderly inpatients under s.5(2) regained their voluntary status, while 57% were detained under another section by the end of the 72 hours (p < 0.05). Duration in hospital prior to applying s.5(2), clinical diagnosis of functional mental illness and use of s.5(4) appear to increase the likelihood of converting s.5(2) into other sections. The high rate of non-conversion of s.5(2) in the elderly to s.2 or 3 may imply that in almost half of the cases, emergency detention may have been used to control isolated incidents of disturbed behaviour in otherwise co-operative patients. Educating doctors and nurses in guidance put forward by the Code of Practice (1993) remains, probably, the main key to a better use of emergency holding powers.

The use of supportive observations within an inpatient mental health unit for older people and dilemma of using the Mental Health Act (2007) or the Mental Capacity Act (2005) in England and Wales.

In England and Wales the interface between the Mental Capacity Act 2005 (MCA) and Mental Health Act 2007 (MHA) is frequently encountered in mental health practice. In services involving older adults many service users will have cognitive impairment and dementias in some instances with behavioural and psychological symptoms of dementia and assessments regarding their mental capacity to make decisions are frequently required. Service users with these illnesses are admitted to psychiatric wards and occasionally nursed under 'close observations' in order to maintain their safety and that of others. The concepts of 'complete and effective control' which may be exercised by ward staff in these circumstances, and the resulting 'loss of autonomy under supervision and control' must be understood in consideration of whether a 'deprivation of liberty' should ensue, particularly when they do not have mental capacity to make decisions about the observations. The observation policy must clearly delineate the different forms of nursing observations possible e.g. close, constant, intermediate, general etc. to avoid confusion among staff members implementing the observation plan. Various dilemmas and management of such dilemmas concerning the use of MCA 2005, MHA 2007 and observation policies has been discussed in this paper. Nursing staff working in both psychiatric and acute hospitals need training in concepts of MCA 2005, MHA 2007 and Deprivation of Liberty Safeguards.

Age and methods of fatal self harm (FSH). Is there a link?

OBJECTIVES: To examine the methods of fatal self harm (FSH) used by the elderly compared to young adults. METHODS: We compared the methods of FSH used by all the elderly over 60 years of age to those used by all younger adults, over 16 and under 60, in the city of Birmingham and Solihull over a period of 4 years, 1995-1998. We applied the term FSH to all deceased who were subjects of Coroner's inquests and attracted verdicts of suicide and open verdicts. FINDINGS: A significantly higher proportion of the elderly who fatally harmed themselves did so by drowning and asphyxia compared to the younger age group (p < 0.05 and p < 0.01, respectively). Significantly more women over the age of 60 committed acts of FSH by tying a plastic bag around the neck than those under 60 (p < 0.05). Method of death was not ascertained in a much higher proportion of elderly FSH (p < 0.01). The most common method of suicide among elderly men and women were hanging and self-poisoning by overdose, respectively. CONCLUSION: The study shows that the most common method of suicide in the elderly is poisoning by drug overdose. It raises the question about the quantity of drugs prescribed for the elderly, e.g. antidepressants, sedatives and pain killers. The study did not confirm previous reports that violent methods are used more frequently with increasing age.

Brain weight in suicide. An exploratory study.

BACKGROUND: There is little available literature on the effect of suicide methods on brain weight. AIMS: To explore variations in post-mortem brain weight in different methods of fatal self-harm (FSH) and in deaths from natural causes. METHOD: A review of a sample of coroners' records of elderly persons (60 and above). Verdicts of suicide, misadventure and open verdicts were classified as FSH. Post-mortem brain weight for 142 FSH victims and 150 victims of unexpected, sudden or unexplained death due to natural causes, and from various methods of FSH, were compared. RESULTS: Brain weight of victims of FSH was significantly higher than of those who died of natural causes (P < 0.01); brain weights in both groups were within the normal range for this age group. There was no significant difference in brain weight between different methods of FSH (P > 0.05). CONCLUSIONS: The findings require critical examination and further research, to include data from younger age groups. A regional or national suicide neuropathological database could be set up if all victims of FSH underwent routine neurohistochemical post-mortem examination.

Tumor debulking followed by immediate combination chemotherapy in advanced ovarian carcinoma. Phase II.

Fifty-one consecutive, previously untreated patients with FIGO stage III or IV epithelial ovarian carcinoma were enrolled in a prospective study over a period of 7 years (1981-1988). Significant improvement has been noted in patients with advanced ovarian cancer following the administration of modified PAC 1 (adriamycin, cytoxan and cyclophosphamide) immediately following primary debulking surgery (within 24 hours) and repeated for 11 monthly cycles. A second look operation was found as an important prognostic indicator. Thirty-one patients (all Stage III) completed the chemotherapy course and were eligible for second look operation. Of these, 21 patients (68%) showed negative second look. Of the patients with negative second look, 17 of 21 (81%) are alive with a mean survival of 61 months (range 19-103 months) after diagnosis. Among those with positive second look only 3 of 10 are alive with a mean of 41 months after diagnosis. The remaining 20 patients (13 stage III and 7 stage IV) did not undergo second look laparotomy. Only 2 of these 20 patients are alive with a mean of 35 months after diagnosis. Other factors of significant importance were: age and completion of chemotherapy course. Patients appeared to benefit from the combined regimen of optimal debulking surgery, completion of 12 courses of chemotherapy with the first course administered immediately after surgery and second look operation. Tumor type or histologic grade did not seem to influence results. The early use of chemotherapy was well tolerated and toxicity was minimal and acceptable.

Lipid associated sialic acid in plasma in patients with advanced carcinoma of the ovaries.

Plasma lipid associated sialic acid (LASA-P) was evaluated in relation to disease status and disease progression in a total of 52 consecutive patients with advanced carcinoma of the ovaries (FIGO stage III and IV). Forty-three individuals with benign gynecologic diseases served as controls. There were three groups. Group 1 included 23 untreated patients who had LASA-P values above normal before debulking operations. Group 2 consisted of 12 patients who completed 12 courses of chemotherapy after debulking operations and presented with negative findings at second look operation (SLO). LASA-P levels were measured in these patients prior to SLO. Eight of 12 patients had normal LASA-P values for a specificity rate of 67 per cent. Four patients had elevated values with no clinical evidence of disease. Group 3 had 17 patients who failed to respond to cytotoxic chemotherapy after initial debulking procedures. All patients in this group had persistent or recurrent disease that was documented at re-exploration or at SLO. Elevated LASA-P levels were noted in 14 of 17 patients for a sensitivity rate of 82 per cent. Rising LASA-P values in serial samples were the only signs of disease recurrence in three of five patients who completed 12 courses of chemotherapy and in whom SLO showed surgical evidence of disease. The predictive value for positive and negative results for all patients were 92.2 and 72.7 per cent, respectively. In spite of the relatively low sensitivity and specificity rates in groups 2 and 3, LASA-P can be used successfully as a valuable adjunct to monitor the course of the disease during treatment in patients with advanced carcinoma of the ovaries.

Stage IV endometrial carcinoma in a 25-year-old woman: a case report and review of the literature.

Presented is a case of endometrial adenocarcinoma FIGO stage IV grade III in a 25-year-old woman with no evidence of any associated disease or known risk factors. To the best of the authors' knowledge this association has not been reported previously.

The feasibility of early administration of combination chemotherapy following cytoreductive surgery and second-look operation in patients with stage III ovarian carcinoma: a pilot study.

The purpose of this study is to evaluate the feasibility of early use of modified PAC-1 chemotherapy following debulking surgery and its efficacy by assessing disease status during a second-look operation. Twenty-six consecutive previously untreated patients with stage III ovarian carcinoma were evaluated in a prospective study over the 5-year period March 1981 to August 1986. Initial exploratory laparotomy was performed for staging and maximum cytoreduction. Within 24 hr postoperative modified PAC-1 (M-PAC-1) combination chemotherapy was administered and then repeated every 4 weeks for 11 months which was then followed by second-look operation. Patients were analyzed according to the following pretreatment characteristics: age, FIGO stage, histologic tumor type, extent of initial surgery, size of residual tumor, and findings during second-look. Nineteen patients were evaluable. No evidence of either microscopic or macroscopic disease was noted in 15 patients (79%), whereas the remaining 4 (21%) exhibited persistent disease. Of the remaining 7 patients not undergoing SLO, 4 completed 12 courses of chemotherapy but did not undergo surgery for medical reason (n = 2) or patient refusal (n = 2). Two more patients refused chemotherapy after 9 courses and the seventh patient expired with persistent disease after 8 courses. The early use of combination chemotherapy was well tolerated. Neurological, hematological, and renal toxicity was never severe enough to cause discontinuation of therapy.