Abnormal pap smear and cervical cancer in pregnancy.

Pregnancy represents a unique opportunity to screen reproductive age women for cervical cancer and abnormal cervical cytology is relatively common in this population. In the absence of large, prospective clinical trials investigating the optimal management strategies for cervical dysplasia in pregnant women, consensus guidelines established by the American Society for Colposcopy and Cervical Pathology is available with considerations to this special patient population. Modalities for evaluation and management algorithms are reviewed and summarized from largely case series of pregnant women with cervical dysplasia and cervical cancer.

Mutation and polymorphism spectrum in osteogenesis imperfecta type II: implications for genotype-phenotype relationships.

Osteogenesis imperfecta (OI), also known as brittle bone disease, is a clinically and genetically heterogeneous disorder primarily characterized by susceptibility to fracture. Although OI generally results from mutations in the type I collagen genes, COL1A1 and COL1A2, the relationship between genotype and phenotype is not yet well understood. To provide additional data for genotype-phenotype analyses and to determine the proportion of mutations in the type I collagen genes among subjects with lethal forms of OI, we sequenced the coding and exon-flanking regions of COL1A1 and COL1A2 in a cohort of 63 subjects with OI type II, the perinatal lethal form of the disease. We identified 61 distinct heterozygous mutations in type I collagen, including five non-synonymous rare variants of unknown significance, of which 43 had not been seen previously. In addition, we found 60 SNPs in COL1A1, of which 17 were not reported previously, and 82 in COL1A2, of which 18 are novel. In three samples without collagen mutations, we found inactivating mutations in CRTAP and LEPRE1, suggesting a frequency of these recessive mutations of approximately 5% in OI type II. A computational model that predicts the outcome of substitutions for glycine within the triple helical domain of collagen alpha1(I) chains predicted lethality with approximately 90% accuracy. The results contribute to the understanding of the etiology of OI by providing data to evaluate and refine current models relating genotype to phenotype and by providing an unbiased indication of the relative frequency of mutations in OI-associated genes.

Recurrence of perinatal lethal osteogenesis imperfecta in sibships: parsing the risk between parental mosaicism for dominant mutations and autosomal recessive inheritance.

PURPOSE: Recurrence of lethal osteogenesis imperfecta in families results from either dominant (parental mosaicism) or recessive inheritance. The proportion of these two mechanisms is not known, and determination of the contribution of each is important to structure genetic counseling for these families. METHODS: We measured the recurrence rate of lethal osteogenesis imperfecta after the birth of an affected infant. We determined the rate of parental mosaicism in a subset of families in which we had identified dominant mutations. In 37 families in which two or more affected infants were born, we identified mutations and determined the proportion that resulted from recessive inheritance. RESULTS: The recurrence rate after the first affected pregnancy was 1.3%. The rate of parental mosaicism in families in which a dominant mutation was identified in a first affected child was 16%. In 37 families with two affected infants, 26 had dominant mutations, seven had recessive mutations, and we failed to find mutations in four. The overall recurrence rate for couples after two or more affected infants was 32%; 27% for families with parental mosaicism, 31% for recessive mutations, and 50% for families with no identified mutation. CONCLUSIONS: In most populations, recurrence of lethal osteogenesis imperfecta usually results from parental mosaicism for dominant mutations, but the carrier frequency of recessive forms of osteogenesis imperfecta will alter that proportion. Mutation identification is an important tool to assess risk and facilitate prenatal or preimplantation diagnosis.

Performance of serum CA125 as a prognostic biomarker in patients with uterine papillary serous carcinoma.

HYPOTHESIS: Serum CA125 is a potential biomarker for metastatic disease and recurrence in patients with uterine papillary serous carcinoma (UPSC). METHODS: All patients with UPSC who had preoperative CA125 measurement and surgical staging between 1998 and 2008 at the participating institutions were included in this analysis (N = 52). Data were extracted from patients' records. Fisher exact and χ² tests were used to assess the association of CA125 levels with clinical and pathological variables. The correlation between CA125 levels (high/low) and lymph node metastases (positive/negative) was evaluated using Spearman correlation coefficients. The association of CA125 elevation with recurrence-free survival was assessed using Cox proportional hazards regression modeling. RESULTS: Preoperative CA125 elevation (>30 U/mL) was observed in 9 (17%) patients and was associated with advanced International Federation of Gynecologists and Obstetricians (FIGO) stage III/IV disease (P = 0.002), lymph node involvement (P = 0.007), and presence of omental metastases (P = 0.001). Disease recurrence and survival data were available for 51 of the 52 patients. During a mean follow-up time of 36 months, 15 (29%) patients experienced disease recurrence and 10 (19%) patients died. There was a moderate positive correlation between CA125 levels and lymph node metastases (r² = 0.39). On multivariate survival analysis, an elevated CA125 level compared to nonelevated CA-125 was not associated with disease recurrence (hazard ratio, 1.61; 95% confidence interval, 0.55-4.77). CONCLUSIONS: Preoperative CA125 levels were significantly associated with metastatic disease in patients with UPSC. However, in this study of surgically staged UPSC patients, preoperative CA125 elevation was not an independent predictor of disease recurrence.

Essential requirements for establishing and operating data trusts: practical guidance co-developed by representatives from fifteen canadian organizations and initiatives.

INTRODUCTION: Increasingly, the label "data trust" is being applied to repeatable mechanisms or approaches to sharing data in a timely, fair, safe, and equitable way. However, there is an absence of practical guidance regarding how to establish and operate a data trust. AIM AND APPROACH: In December 2019, the Canadian Institute for Health Information and the Vector Institute for Artificial Intelligence convened a working meeting of 19 people representing 15 Canadian organizations/initiatives involved in data sharing, most of which focus on public sector health data. The objective was to identify essential requirements for the establishment and operation of data trusts in the Canadian context. Preliminary requirements were discussed during the meeting and then refined as authors contributed to this manuscript. RESULTS: Twelve minimum specification requirements ("min specs") for data trusts were identified. The foundational min spec is that data trusts must meet all legal requirements, including legal authority to collect, hold or share data. In addition, there was agreement that data trusts must have (i) an accountable governing body to ensure that the data trust achieves its stated purpose and is transparent, (ii) comprehensive data management including clear processes and qualified individuals responsible for the collection, storage, access, disclosure and use of data, (iii) training and accountability requirements for all data users and (iv) ongoing public and stakeholder engagement. CONCLUSIONS: Practical guidance for the establishment and operation of data trusts was articulated in the form of 12 min specs requirements. The 12 min specs are a starting point. Future work to refine and strengthen them with members of the public, companies, and additional research data stakeholders from within and outside of Canada, is recommended.

Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch syndrome.

BACKGROUND: Women with the Lynch syndrome (hereditary nonpolyposis colorectal cancer) have a 40 to 60 percent lifetime risk of endometrial cancer and a 10 to 12 percent lifetime risk of ovarian cancer. The benefit of prophylactic gynecologic surgery for women with this syndrome has been uncertain. We designed this study to determine the reduction in the risk of gynecologic cancers associated with prophylactic hysterectomy and bilateral salpingo-oophorectomy in women with the Lynch syndrome. METHODS: Three hundred fifteen women with documented germ-line mutations associated with the Lynch syndrome were identified. Women who had undergone prophylactic hysterectomy (61 women) and women who had undergone prophylactic bilateral salpingo-oophorectomy (47 women) were matched with mutation-positive women who had not undergone the procedure in question (210 women for the analysis of endometrial cancer and 223 for the analysis of ovarian cancer). Women who had undergone prophylactic surgery and their matched controls were followed from the date of the surgery until the occurrence of cancer or until the data were censored at the time of the last follow-up visit. RESULTS: There were no occurrences of endometrial, ovarian, or primary peritoneal cancer among the women who had undergone prophylactic surgery. Endometrial cancer was diagnosed in 69 women in the control group (33 percent), for an incidence density of 0.045 per woman-year, yielding a prevented fraction (the proportion of potential new cancers prevented) of 100 percent (95 percent confidence interval, 90 to 100 percent). Ovarian cancer was diagnosed in 12 women in the control group (5 percent), for an incidence density of 0.005 per woman-year, yielding a prevented fraction of 100 percent (95 percent confidence interval, -62 to 100 percent). CONCLUSIONS: These findings suggest that prophylactic hysterectomy with bilateral salpingo-oophorectomy is an effective strategy for preventing endometrial and ovarian cancer in women with the Lynch syndrome.

Substitutions for arginine at position 780 in triple helical domain of the α1(I) chain alter folding of the type I procollagen molecule and cause osteogenesis imperfecta.

OI is a clinically and genetically heterogeneous disorder characterized by bone fragility. More than 90% of patients are heterozygous for mutations in type I collagen genes, COL1A1 and COL1A2, and a common mutation is substitution for an obligatory glycine in the triple helical Gly-X-Y repeats. Few non-glycine substitutions in the triple helical domain have been reported; most result in Y-position substitutions of arginine by cysteine. Here, we investigated leucine and cysteine substitutions for one Y-position arginine, p.Arg958 (Arg780 in the triple helical domain) of proα1(I) chains that cause mild OI. We compared their effects with two substitutions for glycine located in close proximity. Like substitutions for glycine, those for arginine reduced the denaturation temperature of the whole molecule and caused asymmetric posttranslational overmodification of the chains. Circular dichroism and increased susceptibility to cleavage by MMP1, MMP2 and catalytic domain of MMP1 revealed significant destabilization of the triple helix near the collagenase cleavage site. On a cellular level, we observed slower triple helix folding and intracellular collagen retention, which disturbed the Endoplasmic Reticulum function and affected matrix deposition. Molecular dynamic modeling suggested that Arg780 substitutions disrupt the triple helix structure and folding by eliminating hydrogen bonds of arginine side chains, in addition to preventing HSP47 binding. The pathogenic effects of these non-glycine substitutions in bone are probably caused mostly by procollagen misfolding and its downstream effects.

Consortium for osteogenesis imperfecta mutations in the helical domain of type I collagen: regions rich in lethal mutations align with collagen binding sites for integrins and proteoglycans.

Osteogenesis imperfecta (OI) is a generalized disorder of connective tissue characterized by fragile bones and easy susceptibility to fracture. Most cases of OI are caused by mutations in type I collagen. We have identified and assembled structural mutations in type I collagen genes (COL1A1 and COL1A2, encoding the proalpha1(I) and proalpha2(I) chains, respectively) that result in OI. Quantitative defects causing type I OI were not included. Of these 832 independent mutations, 682 result in substitution for glycine residues in the triple helical domain of the encoded protein and 150 alter splice sites. Distinct genotype-phenotype relationships emerge for each chain. One-third of the mutations that result in glycine substitutions in alpha1(I) are lethal, especially when the substituting residues are charged or have a branched side chain. Substitutions in the first 200 residues are nonlethal and have variable outcome thereafter, unrelated to folding or helix stability domains. Two exclusively lethal regions (helix positions 691-823 and 910-964) align with major ligand binding regions (MLBRs), suggesting crucial interactions of collagen monomers or fibrils with integrins, matrix metalloproteinases (MMPs), fibronectin, and cartilage oligomeric matrix protein (COMP). Mutations in COL1A2 are predominantly nonlethal (80%). Lethal substitutions are located in eight regularly spaced clusters along the chain, supporting a regional model. The lethal regions align with proteoglycan binding sites along the fibril, suggesting a role in fibril-matrix interactions. Recurrences at the same site in alpha2(I) are generally concordant for outcome, unlike alpha1(I). Splice site mutations comprise 20% of helical mutations identified in OI patients, and may lead to exon skipping, intron inclusion, or the activation of cryptic splice sites. Splice site mutations in COL1A1 are rarely lethal; they often lead to frameshifts and the mild type I phenotype. In alpha2(I), lethal exon skipping events are located in the carboxyl half of the chain. Our data on genotype-phenotype relationships indicate that the two collagen chains play very different roles in matrix integrity and that phenotype depends on intracellular and extracellular events.

Gynecologic cancer prevention in Lynch syndrome/hereditary nonpolyposis colorectal cancer families.

OBJECTIVE: Women from Lynch syndrome/hereditary nonpolyposis colorectal cancer (Lynch/HNPCC) families have an increased lifetime risk of developing endometrial and ovarian cancer. This study models a comparison of management strategies for women who carry a Lynch/HNPCC mutation. METHODS: A decision analytic model with three arms was designed to compare annual gynecologic examinations with annual screening (ultrasonography, endometrial biopsy, CA 125) and with hysterectomy with bilateral salpingo-oophorectomy at age 30 years The existing literature was searched for studies on the accuracy of endometrial and ovarian cancer screening using endometrial biopsy, transvaginal ultrasonography, and serum CA 125. The Surveillance, Epidemiology and End Results database from 1988 to 2001 was used to estimate cancer mortality outcomes. RESULTS: In the surgical arm, 0.0056% of women were diagnosed with ovarian cancer and 0.0060% of women with endometrial cancer. These numbers increased to 3.7% and 18.4% in women being screened, and 8.3% and 48.7% in women undergoing annual examinations, respectively. Surgical management led to the longest expected survival time at 79.98 years, followed by screening at 79.31 years, and annual examinations at 77.41 years. If starting at age 30 and discounting life years at 3%, surgery still leads to the greatest expected life years. When comparing prophylactic surgery with the screening option, one would need to perform 75 surgeries to save one woman's entire life. For cancer prevention, however, only 28 and 6 prophylactic surgeries would need to be performed to prevent one case of ovarian and endometrial cancer, respectively. CONCLUSION: Risk-reducing hysterectomy and bilateral salpingo-oophorectomy may be considered in women with Lynch/HNPCC to prevent gynecologic cancers and their associated morbidities.

Awareness of gynecologic surveillance in women from hereditary non-polyposis colorectal cancer families.

OBJECTIVE: To determine knowledge of gynecologic cancer risk and screening in women with HNPCC. STUDY DESIGN: Forty-three women with HNPCC were counseled through a gastrointestinal cancer risk program, and later sent a questionnaire regarding their screening practices for gynecologic neoplasms. RESULTS: Twenty-seven (63%) of 43 responded. Fifteen (55%) of 27 had previously been diagnosed with cancer. Among 16 women with a uterus, 11 (69%) reported surveillance by ultrasound or endometrial sampling. Among 21 respondents with ovaries, 13 (62%) reported screening by ultrasound or CA125. Twenty-two (81%) of 27 had seen a gynecologist after receiving their HNPCC diagnosis, but only 12% recalled hearing about risks from their gynecologist, and 8% from their gynecologic oncologist. Genetic counselors were cited as the most common source (48%) of gynecologic cancer risk information. CONCLUSIONS: While the effectiveness of surveillance remains in question, gynecologists can be a source of information regarding gynecologic cancer risk for women from HNPCC families.

A cost-effectiveness analysis of prophylactic surgery versus gynecologic surveillance for women from hereditary non-polyposis colorectal cancer (HNPCC) Families.

Women at risk for Lynch Syndrome/HNPCC have an increased lifetime risk of endometrial and ovarian cancer. This study investigates the cost-effectiveness of prophylactic surgery versus surveillance in women with Lynch Syndrome. A decision analytic model was designed incorporating key clinical decisions and existing probabilities, costs, and outcomes from the literature. Clinical forum where risk-reducing surgery and surveillance were considered. A theoretical population of women with Lynch Syndrome at age 30 was used for the analysis. A decision analytic model was designed comparing the health outcomes of prophylactic hysterectomy with bilateral salpingo-oophorectomy at age 30 versus annual gynecologic screening versus annual gynecologic exam. The literature was searched for probabilities of different health outcomes, results of screening modalities, and costs of cancer diagnosis and treatment. Cost-effectiveness expressed in dollars per discounted life-years. Risk-reducing surgery is the least expensive option, costing $23,422 per patient for 25.71 quality-adjusted life-years (QALYs). Annual screening costs $68,392 for 25.17 QALYs; and annual examination without screening costs $100,484 for 24.60 QALYs. Further, because risk-reducing surgery leads to both the lowest costs and the highest number of QALYs, it is a dominant strategy. Risk-reducing surgery is the most cost-effective option from a societal healthcare cost perspective.