Follow-up of patients who are clinically disease-free after primary treatment for fallopian tube, primary peritoneal, or epithelial ovarian cancer: a Program in Evidence-Based Care guideline adaptation.

BACKGROUND: A need for follow-up recommendations for survivors of fallopian tube, primary peritoneal, or epithelial ovarian cancer after completion of primary treatment was identified by Cancer Care Ontario's Program in Evidence-Based Care. METHODS: We searched for existing guidelines, conducted a systematic review (medline, embase, and cdsr, January 2010 to March 2015), created draft recommendations, and completed a comprehensive review process. Outcomes included overall survival, quality of life, and patient preferences. RESULTS: The Cancer Australia guidance document Follow Up of Women with Epithelial Ovarian Cancer was adapted for the Ontario context. A key randomized controlled trial found that the overall survival rate did not differ between asymptomatic women who received early treatment based on elevated serum cancer antigen 125 (ca125) alone and women who waited for the appearance of clinical symptoms before initiating treatment (hazard ratio: 0.98; 95% confidence interval: 0.80 to 1.20; p = 0.85); in addition, patients in the delayed treatment group reported good global health scores for longer. No randomized studies were found for other types of follow-up. We recommend that survivors be made aware of the potential harms and benefits of surveillance, including a discussion of the limitations of ca125 testing. Women could be offered the option of no formal follow-up or a follow-up schedule that is agreed upon by the woman and her health care provider. Education about the most common symptoms of recurrence should be provided. Alternative models of care such as nurse-led or telephone-based follow-up (or both) could be emerging options. CONCLUSIONS: The recommendations provided in this guidance document have a limited evidence base. Recommendations should be updated as further information becomes available.

Survival benefit of repeat liver transplantation in the United States: a serial MELD analysis by hepatitis C status and donor risk index.

Survival benefit (SB) for first liver transplantation (LT) is favorable at Model for End-Stage Liver Disease (MELD)≥15. Herein, we identify the MELD threshold for SB from repeat liver transplantation (ReLT) by recipient hepatitis C virus (HCV) status and donor risk index (DRI). We analyzed lab MELD scores in new United Network for Organ Sharing registrants for ReLT from March 2002 to January 2010. Risk of ReLT graft failure≤1 year versus waitlist mortality was calculated using Cox regression, adjusting for recipient characteristics. Of 3057 ReLT candidates, 54% had HCV and 606 died while listed. There were 1985 ReLT recipients, 52% had HCV and 567 ReLT graft failures by 1 year. Unadjusted waitlist mortality and post-ReLT graft failure rates were 416 (95% confidence interval [CI] 384-450) and 375 (95% CI 345-407) per 1000 patient-years, respectively. Waitlist mortality was higher with increasing waitlist MELD (p<0.001). The MELD for SB from ReLT overall was 21 (21 in non-HCV and 24 in HCV patients). MELD for SB varied by DRI in HCV patients (MELD 21, 24 and 27 for low, medium and high DRI, respectively) but did not vary for non-HCV patients. Compared to first LT, ReLT requires a higher MELD threshold to achieve an SB resulting in a narrower therapeutic window to optimize the utility of scarce liver grafts.

Management of a suspicious adnexal mass: a clinical practice guideline.

QUESTIONS: What is the optimal strategy for preoperative identification of the adnexal mass suspicious for ovarian cancer? What is the most appropriate surgical procedure for a woman who presents with an adnexal mass suspicious for malignancy? PERSPECTIVES: In Canada in 2010, 2600 new cases of ovarian cancer were estimated to have been diagnosed, and of those patients, 1750 were estimated to have died, making ovarian cancer the 7th most prevalent form of cancer and the 5th leading cause of cancer death in Canadian women. Women with ovarian cancer typically have subtle, nonspecific symptoms such as abdominal pain, bloating, changes in bowel frequency, and urinary or pelvic symptoms, making early detection difficult. Thus, most ovarian cancer cases are diagnosed at an advanced stage, when the cancer has spread outside the pelvis. Because of late diagnosis, the 5-year relative survival ratio for ovarian cancer in Canada is only 40%. Unfortunately, because of the low positive predictive value of potential screening tests (cancer antigen 125 and ultrasonography), there is currently no screening strategy for ovarian cancer. The purpose of this document is to identify evidence that would inform optimal recommended protocols for the identification and surgical management of adnexal masses suspicious for malignancy. OUTCOMES: Outcomes of interest for the identification question included sensitivity and specificity. Outcomes of interest for the surgical question included optimal surgery, overall survival, progression-free or disease-free survival, reduction in the number of surgeries, morbidity, adverse events, and quality of life. METHODOLOGY: After a systematic review, a practice guideline containing clinical recommendations relevant to patients in Ontario was drafted. The practice guideline was reviewed and approved by the Gynecology Disease Site Group and the Report Approval Panel of the Program in Evidence-based Care. External review by Ontario practitioners was obtained through a survey, the results of which were incorporated into the practice guideline. PRACTICE GUIDELINE: These recommendations apply to adult women presenting with a suspicious adnexal mass, either symptomatic or asymptomatic. IDENTIFICATION OF AN ADNEXAL MASS SUSPICIOUS FOR OVARIAN CANCER: Sonography (particularly 3-dimensional sonography), magnetic resonance imaging (mri), and computed tomography (ct) imaging are each recommended for differentiating malignant from benign ovarian masses. However, the working group offers the following further recommendations, based on their expert consensus opinion and a consideration of availability, access, and harm: Where technically feasible, transvaginal sonography should be the modality of first choice in patients with a suspicious isolated ovarian mass.To help clarify malignant potential in patients in whom ultrasonography may be unreliable, mri is the most appropriate test.In cases in which extra-ovarian disease is suspected or needs to be ruled out, ct is the most useful technique.Evaluation of an adnexal mass by Doppler technology alone is not recommended. Doppler technology should be combined with a morphology assessment.Ultrasonography-based morphology scoring systems can be used to differentiate benign from malignant adnexal masses. These scoring systems are based on specific ultrasound parameters, each with several scores base on determined features. All evaluated scoring systems were found to have an acceptable level of sensitivity and specificity; the choice of scoring system may therefore be made based on clinician preference.As a standalone modality, serum cancer antigen 125 is not recommended for distinguishing between benign and malignant adnexal masses.Frozen sections for the intraoperative diagnosis of a suspicious adnexal mass is recommended in settings in which availability and patient preference allow. SURGICAL PROCEDURES FOR AN ADNEXAL MASS SUSPICIOUS FOR MALIGNANCY: To improve survival, comprehensive surgical staging with lymphadenectomy is recommended for the surgical management of patients with early-stage ovarian cancer. Laparoscopy is a reasonable alternative to laparotomy, provided that appropriate surgery and staging can be done. The choice between laparoscopy and laparotomy should be based on patient and clinician preference. Discussion with a gynecologic oncologist is recommended. Fertility-preserving surgery is an acceptable alternative to more extensive surgery in patients with low-malignant-potential tumours and those with well-differentiated surgical stage i ovarian cancer. Discussion with a gynecologic oncologist is recommended.

Recommendations for the classification of diseases as CFTR-related disorders.

Several diseases have been clinically or genetically related to cystic fibrosis (CF), but a consensus definition is lacking. Here, we present a proposal for consensus guidelines on cystic fibrosis transmembrane conductance regulator (CFTR)-related disorders (CFTR-RDs), reached after expert discussion and two dedicated workshops. A CFTR-RD may be defined as "a clinical entity associated with CFTR dysfunction that does not fulfil diagnostic criteria for CF". The utility of sweat testing, mutation analysis, nasal potential difference, and/or intestinal current measurement for the differential diagnosis of CF and CFTR-RD is discussed. Algorithms which use genetic and functional diagnostic tests to distinguish CF and CFTR-RDs are presented. According to present knowledge, congenital bilateral absence of vas deferens (CBAVD), acute recurrent or chronic pancreatitis and disseminated bronchiectasis, all with CFTR dysfunction, are CFTR-RDs.

Diagnosis of epithelial ovarian carcinoma prior to neoadjuvant chemotherapy.

OBJECTIVE: There are no evidence based guidelines for the diagnosis of epithelial ovarian cancer (EOC) prior to the initiation of neoadjuvant chemotherapy. The aim of this study was to review our diagnostic practice, provide guidelines for clinical practice, and suggest a diagnostic strategy for validation in future prospective trials. PATIENTS AND METHODS: A retrospective chart review of patients undergoing neoadjuvant chemotherapy followed by debulking surgery was performed. Final diagnoses were based on expert pathology review of surgical specimens. Diagnostic strategies were defined as histologic, cytologic and clinical. Performance of these strategies in predicting final pathology was compared. RESULTS: Between 1994 and 2007, 149 patients were identified. Initial diagnosis was made on the basis of: cytology (paracentesis, thoracentesis, or fine needle aspirate) 72% (108 patients); histology (core biopsy, surgery) 18% (26), clinical (Radiology and CA-125) 10% (15). The final diagnosis was consistent with invasive EOC in 96% of patients. The diagnostic accuracies of the 3 strategies were: cytology 98%, histology 92%, and clinical 87%, (p=0.04). Specific EOC subtype was identified in 59% of patients (histology 77% and cytology 55%). When available, the initial subtype corresponded to the final subtype in 85% of cases: histology 80%, cytology 86%. CONCLUSION: Diagnosis of epithelial ovarian cancer based on cytology and histology are superior to clinical factors alone. In a centre with trained gynecologic cytopathologists, a diagnosis of EOC by cytology is not significantly inferior to a diagnosis made by histology. These data are important for clinical practice and the design of future clinical trials.

Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice.

It is often challenging for the clinician interested in cystic fibrosis (CF) to interpret molecular genetic results, and to integrate them in the diagnostic process. The limitations of genotyping technology, the choice of mutations to be tested, and the clinical context in which the test is administered can all influence how genetic information is interpreted. This paper describes the conclusions of a consensus conference to address the use and interpretation of CF mutation analysis in clinical settings. Although the diagnosis of CF is usually straightforward, care needs to be exercised in the use and interpretation of genetic tests: genotype information is not the final arbiter of a clinical diagnosis of CF or CF transmembrane conductance regulator (CFTR) protein related disorders. The diagnosis of these conditions is primarily based on the clinical presentation, and is supported by evaluation of CFTR function (sweat testing, nasal potential difference) and genetic analysis. None of these features are sufficient on their own to make a diagnosis of CF or CFTR-related disorders. Broad genotype/phenotype associations are useful in epidemiological studies, but CFTR genotype does not accurately predict individual outcome. The use of CFTR genotype for prediction of prognosis in people with CF at the time of their diagnosis is not recommended. The importance of communication between clinicians and medical genetic laboratories is emphasized. The results of testing and their implications should be reported in a manner understandable to the clinicians caring for CF patients.

The selective oestrogen receptor modulator, LY362321, is not neuroprotective in a rat model of transient focal ischaemia.

Selective oestrogen receptor modulators (SERMs) may offer improved alternatives to oestrogen as neuroprotectants in experimental stroke. The present study investigated the role of a novel SERM, LY362321, in a rat model of transient middle cerebral artery occlusion (MCAO). Female Sprague-Dawley rats were ovariectomised and began receiving daily s.c. injections of either 1 mg/kg (n = 13), 10 mg/kg (n = 14) of LY362321, or vehicle (n = 13). The left MCA was temporarily occluded (90 min), with cortical blood flow monitoring, at 12 days post ovariectomy. Sensorimotor function was assessed using a neurological score prior to the MCAO and daily for 3 days following the MCAO. Tissue was processed for infarct volume assessment using 2,3,5-triphenyltetra-zolium chloride staining. The results indicated that there were no significant differences amongst groups in cortical blood flow during the MCAO. Furthermore, there was no significant difference in infarct size amongst vehicle, 1, and 10 mg/kg treated animals: 22.9 +/- 5.0, 16.7 +/- 4.2, and 21.1 +/- 4.1, respectively, one-way anova [F(2,32) = 0.542, P = 0.587]. The MCAO induced a significant decline in neurological score in the vehicle group (from 14 to 7 at 24 h post-MCAO) but this was not significantly affected by LY362321 at either dose. In conclusion, pretreatment with a low or high dose of the novel SERM LY362321 did not significantly influence cerebral blood flow, infarct volume, or sensorimotor function in rats exposed to transient MCAO.

Cystic fibrosis mortality and survival in the UK: 1947-2003.

Data up to 1995 on the survival of 3-yr cohorts of patients with cystic fibrosis (CF) born in the UK in the period 1968-1992 have previously been published. The present study reports survival data up to the end of 2003 together with a 2003 population estimate. All subjects with CF born in the UK in the period 1968-1992 were identified up to 1997 by active enquiry through recognised CF clinics and other hospital consultants. Information from the death certification authorities up to the end of 2003 was added. Death certificates that could not be matched with UK Cystic Fibrosis Survey records were investigated and the data reconciled. The observed survival up to 2003 of CF patients born in 1978 was 55% for males and 49% for females. For 1988 and 1992 the data were 91 and 88%, and 97 and 96%, respectively. The estimated 2003 mid-year CF population was 8,284. The continuing improvement in survival of cystic fibrosis patients in successive cohorts means that the previous prediction of median survival of >50 yrs of age for individuals born in 2000 continues to look realistic, even in the absence of proven effective therapy aimed at correcting the basic cystic fibrosis defect.

Shwachman-Diamond syndrome: UK perspective.

So much has been added to our knowledge of Shwachman-Diamond syndrome (SDS) since it was last reviewed in this journal some 25 years ago, that there is now an urgent need to bring the condition to the attention of a new generation of paediatricians. SDS, although a rare autosomal recessive disorder, demands wide attention because it features in the differential diagnosis of a number of important childhood diseases. It can be diagnosed in children of all ages, or in adults. SDS most commonly presents in infancy with features of exocrine pancreatic insufficiency, bone marrow dysfunction, and short stature.

Cystic fibrosis: terminology and diagnostic algorithms.

There is great heterogeneity in the clinical manifestations of cystic fibrosis (CF). Some patients may have all the classical manifestations of CF from infancy and have a relatively poor prognosis, while others have much milder or even atypical disease manifestations and still carry mutations on each of the CFTR genes. It is important to distinguish between these categories of patients. The European Diagnostic Working Group proposes the following terminology. Patients are diagnosed with classic or typical CF if they have one or more phenotypic characteristics and a sweat chloride concentration of >60 mmol/l. The vast majority of CF patients fall into this category. Usually one established mutation causing CF can be identified on each CFTR gene. Patients with classic CF can have exocrine pancreatic insufficiency or pancreatic sufficiency. The disease can have a severe course with rapid progression of symptoms or a milder course with very little deterioration over time. Patients with non-classic or atypical CF have a CF phenotype in at least one organ system and a normal (<30 mmol/l) or borderline (30-60 mmol/l) sweat chloride level. In these patients confirmation of the diagnosis of CF requires detection of one disease causing mutation on each CFTR gene or direct quantification of CFTR dysfunction by nasal potential difference measurement. Non-classic CF includes patients with multiorgan or single organ involvement. Most of these patients have exocrine pancreatic sufficiency and milder lung disease. Algorithms for a structured diagnostic process are proposed.

Differential effects of estrogen and raloxifene on messenger RNA and matrix metalloproteinase 2 activity in the rat uterus.

A detailed analysis of the differential effects of estrogen (E) compared to raloxifene (Ral), a selective estrogen receptor modulator (SERM), following estrogen receptor (ER) binding in gynecological tissues was conducted using gene microarrays, Northern blot analysis, and matrix metalloproteinase (MMP) 2 activity studies. We profiled gene expression in the uterus following acute (1 day) and prolonged daily (5 wk) treatment of E and Ral in ovariectomized rats. Estrogen regulated twice as many genes as Ral, largely those associated with catalysis and metabolism, whereas Ral induced genes associated with cell death and negative cell regulation. Follow-up studies confirmed that genes associated with matrix integrity were differentially regulated by Ral and E at various time points in uterine and vaginal tissues. Additional experiments were conducted to determine the levels of MMP2 activity in uterus explants from ovariectomized rats following 2 wk of treatment with E, Ral, or one of two additional SERMs: lasofoxifene, and levormeloxifene. Both E and lasofoxifene stimulated uterine MMP2 activity to a level twofold that of Ral, whereas levormeloxifene elevated MMP2 activity to a level 12-fold that of Ral. These data show that one of the significant differences between E and Ral signaling in the uterus is the regulation of genes and proteins associated with matrix integrity. This may be a potential key difference between the action of SERMs in the uterus of postmenopausal women.

The nongenotropic synthetic ligand 4-estren-3alpha17beta-diol is a high-affinity genotropic androgen receptor agonist.

The nongenotropic ligand estren (Science 298:843-846, 2002) was evaluated for its transcriptional activity mediated by the human androgen receptor (AR). Our results show that estren can bind, translocate, transactivate, and regulate two known target genes of AR in androgen-responsive cell lines. Estren binds recombinant AR with 10-fold higher affinity than either estrogen receptor (ER)-alpha or ERbeta. Estren-bound AR can translocate AR to the nucleus and stimulate the androgen response element-luciferase reporter activity with an efficacy similar to that of androgen. Estren also increased the expression of prostate-specific antigen (PSA) in a dose-dependent manner in human LnCaP cells. Using chromatin immunoprecipitation analysis, we show that the estren-bound AR coimmunoprecipitates with a region of the PSA gene promoter. Therefore, cotreatment with an AR antagonist, bicalutamide, blocked the estren-induced increase in PSA expression. In contrast, phosphoinositol 3-kinase inhibitor wortmannin, or extracellular signal-regulated kinase inhibitor 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophynyltio)butadiene (U0126), and ER antagonist ICI-182780 failed to block the effects of estren. In vivo analysis of estren's action on male-orchidectomized ICR mice revealed estren's AR agonist actions on the levator ani and seminal vesicle target tissues. Taken together, our results reveal the hitherto unidentified genotropic action of estren mediated by AR in androgen-responsive cells and tissues.

Intracerebral transplantation of adult mouse neural progenitor cells into the Niemann-Pick-A mouse leads to a marked decrease in lysosomal storage pathology.

Niemann-Pick disease is caused by a genetic deficiency in acid sphingomyelinase (ASM) leading to the intracellular accumulation of sphingomyelin and cholesterol in lysosomes. In the present study, we evaluated the effects of direct intracerebral transplantation of neural progenitor cells (NPCs) on the brain storage pathology in the ASM knock-out (ASMKO) mouse model of Type A Niemann-Pick disease. NPCs derived from adult mouse brain were genetically modified to express human ASM (hASM) and were transplanted into multiple regions of the ASMKO mouse brain. Transplanted NPCs survived, migrated, and showed region-specific differentiation in the host brain up to 10 weeks after transplantation (the longest time point examined). In vitro, gene-modified NPCs expressed up to 10 times more and released five times more ASM activity into the culture media compared with nontransduced NPCs. In vivo, transplanted cells expressed hASM at levels that were barely detectable by immunostaining but were sufficient for uptake and cross-correction of host cells, leading to reversal of distended lysosomal pathology and regional clearance of sphingomyelin and cholesterol storage. Within the host brain, the area of correction closely overlapped with the distribution of the hASM-modified NPCs. No correction of pathology occurred in brain regions that received transplants of nontransduced NPCs. These results indicate that the presence of transduced NPCs releasing low levels of hASM within the ASMKO mouse brain is necessary and sufficient to reverse lysosomal storage pathology. Potentially, NPCs may serve as a useful gene transfer vehicle for the treatment of CNS pathology in other lysosomal storage diseases and neurodegenerative disorders.

Clinical features and risk of recurrence among patients with vaginal intraepithelial neoplasia.

OBJECTIVE: The best treatment modality and factors affecting recurrence among women with vaginal intraepithelial neoplasia (VAIN) are yet to be determined. The aims of the current study were to describe the clinical features, results of treatment, and factors affecting recurrence among patients with VAIN. METHODS: We conducted a retrospective review of 121 women with VAIN after confirming the histologic diagnosis. Patient demographics, clinical features, and results of therapy were recorded. Factors affecting recurrence were assessed using the odds ratio and the 95% confidence intervals among patients who were followed up for 7 months or more and had at least one posttreatment Papanicolaou smear. Significant univariate odds ratios were assessed jointly in a multivariate model with a stratified analysis. RESULTS: The mean age of the patients was 35.0 (+/-17), 41% of the patients smoked, 39% had a history of human papillomavirus infection, 27% had history of sexually transmitted diseases, 22% had history of surgery for cervical intraepithelial neoplasia (CIN), and 23% had total hysterectomy. The upper third of the vagina was the most common site of VAIN and 61% of the lesions were multifocal. Associated cervical and vulvar intraepithelial neoplasia (VIN) were present in 65 and 10%, respectively. Recurrences of VAIN and progression to invasive vaginal cancer occurred in 33 and 2%, respectively. Recurrences following partial vaginectomy, laser, and 5-fluorouracil were 0, 38, and 59%, respectively (P = 0.0001). Multifocality and method of treatment were significant independent predictors of VAIN recurrences (odds ratio 3.3, 95% CI 1.2, 9.2, P = 0.02, and 22.4, 95% CI 1.3, 393.6, P = 0.001, respectively), with no interaction, based on a stratified analysis. CONCLUSIONS: VAIN occurs most often among women with CIN or VIN, commonly involves the upper third of the vagina, and is often multifocal. Partial vaginectomy provides the highest cure rate and multifocality is a risk factor for recurrence.

Gastrin, somatostatin and infantile hypertrophic pyloric stenosis.

UNLABELLED: Despite multiple and often contradictory research, no firm conclusions regarding the role of hypergastrinaemia in infantile hypertrophic pyloric stenosis (IHPS) have been established. Evaluation of somatostatin, the main physiological antagonist of gastrin, has not been assessed in previous studies. Long-term evaluation following pyloromyotomy suggests persistent abnormalities in gastrin and somatostatin in IHPS. The objective of this case-controlled study was to compare fasting serum gastrin and somatostatin levels in IHPS. Serum sample were collected from 39 children with IHPS at the time of pyloromyotomy and 20 age-matched controls with no evidence of gastrointestinal disease. Standard radioimmunoassay techniques were used to detect circulating levels of the hormones. A two-tailed t-test was used for statistical analysis. The levels of the two hormones (mean +/- SEM) revealed that there was no evidence of hypergastrinaemia in IHPS compared with controls (75.6 +/- 16.1 and 68.1 +/- 7.8 ng l(-1), respectively), but that the level of somatostatin was significantly elevated (38.9 +/- 6.4 and 30.5 +/- 5.8 ng l(-1), p = 0.016). An inverse trend in the gastrin/somatostatin levels could not be identified in IHPS. CONCLUSION: Somatostatin but not gastrin is raised in IHPS. Somatostatin is known to inhibit the actions of inhibitory neurotransmitters in the pylorus and may explain the development of pylorospasm, which is believed to be important in the development of pyloric tumours. These results do not agree with a previous long-term follow-up study, but reflect the hormonal imbalance at the time of pyloric hypertrophy.

KG-1 and KG-1a model the p15 CpG island methylation observed in acute myeloid leukemia patients.

p15 and p16 are tumor suppressor genes that have 5' CpG islands and both are subject to hypermethylation associated with their transcriptional inactivation in hematological malignancies. In this study, we used sodium bisulfite sequencing to obtain a complete map of the 5-methylcytosine status of 80 CpGs covering approximately 900 bp in the 5' p15 CpG island, and 53 CpGs covering approximately 700 bp in the 5' p16 CpG island in the hematopoietic cell lines HL60, KG-1, and KG-1a, two normal human bone marrow samples (NBM), and eight cytosine arabinoside (ara-C)-resistant adult acute myeloid leukemia (AML) patients. We found methylation of the p15 CpG island in 75% of the AML cases studied spread throughout the 5' region analyzed but only minimal methylation of p15 in NBM. Further, the p16 CpG island was not aberrantly methylated in NBM or the eight AML patients studied. Two distinct modes of p15 methylation in AML were identified, variegated and complete. Interestingly, KG-1 and KG-1a model the methylation of p15 observed in AML, where KG-1 methylation is variegated and KG-1a methylation is complete. Both KG-1 and KG-1a had no detectable p15 mRNA or protein. These results demonstrate that rather than continuous increases in p15 methylation, surprisingly two punctuated modes of aberrant p15 methylation, variegated and complete, were observed in vitro and in vivo. Thus aberrant methylation of tumor suppressor genes is not a binary switch but in the case of p15 occurs in two independent and stable states.