Polymorphism in intron 2 of the interleukin-1 receptor antagonist gene, local midtrimester cytokine response to vaginal flora, and subsequent preterm birth

OBJECTIVE: This study investigated the association between polymorphism in intron 2 of the interleukin-1 receptor antagonist gene, midtrimester vaginal microflora, vaginal interleukin receptor antagonist and interleukin-1beta levels and subsequent spontaneous preterm birth. STUDY DESIGN: Vaginal samples from 212 women, collected at 18-22 weeks' gestation, were analyzed for the polymorphism in intron 2 of the interleukin-1 receptor antagonist gene by polymerase chain reaction, qualitative and quantitative vaginal microflora, and interleukin-1beta and interleukin-1ra concentrations by enzyme-linked immunosorbent assay. Pregnancy outcome data were subsequently obtained. RESULTS: Carriage of intron 2 of the interleukin-1 receptor antagonist allele 2 (IL1RN * 2) was associated with an elevated vaginal pH in black ( P < .001) and white ( P = .005) women, a reduced interleukin-1beta response to anaerobic Gram-negative rods and/or Gardnerella vaginalis ( P < .01), and a decreased rate of spontaneous preterm deliveries (6% versus 18%, P = .02). In black women, IL1RN * 2 carriage was associated with increased anaerobic Gram-negative rods, Mycoplasma, and Peptostreptococci and decreased Lactobacilli colonization. CONCLUSION: IL1RN * 2 carriage was associated with a blunted proinflammatory interleukin-1beta response to abnormal vaginal flora. This property may decrease susceptibility to infection-related preterm birth.     

eRFA: Excision Followed by RFA—a New Technique to Improve Local Control in Breast Cancer

Introduction Excision followed by RFA (eRFA) may allow improved cosmesis while ensuring negative margins in patients with breast cancer. This technique utilizes heat to create an additional tumor-free zone around the lumpectomy cavity. We hypothesized that eRFA will decrease the need for re-excision of inadequate margins.Methods Between July 2002 and January 2005, we conducted a multiphase trial of RFA of prophylactic mastectomy specimens and of women desiring lumpectomy. In both models, a lumpectomy was performed, the RFA probe was deployed 1 cm circumferentially into the walls of the lumpectomy cavity and maintained at 100°C for 15 min. Whole mount slides were used to measure the zone of ablation for ex vivo specimens. Hematoxylin and eosin staining of in vivo lumpectomy margins <3 mm was considered inadequate.Results Nineteen prophylactic mastectomy ablations revealed a consistent perimeter of ablation. Forty-one patients (mean age 63 ± 14 years) had an average tumor size of 1.6 ± 1.5 cm underwent in vivo eRFA, and 25% had inadequate margins: one focally positive, one <2 mm, eight <1 mm and one grossly positive. Only the grossly positive margin was re-excised. Overall complication rate of in vivo ablations was 7.5%. Twenty-four of 41 patients did not have post-eRFA XRT. No in-site local recurrences have occurred during a median follow-up of 24 months (12–45 months). Two patients have occurred elsewhere.Conclusions The ex vivo ablation model reliably created a 5–10 mm perimeter of ablation. In vivo, this zone reduced the need for re-excision for inadequate margins by 91% (10/11). Short-term follow-up suggests that eRFA could reduce re-excision surgery and local recurrence.     

Parents’ expectations,preferences, and recall of germline findings in a childhood cancer precision medicine trial

Background

Germline genome sequencing in childhood cancer precision medicine trials may reveal pathogenic or likely pathogenic variants in cancer predisposition genes in more than 10% of children. These findings can have implications for diagnosis, treatment, and the child’s and family’s future cancer risk. Understanding parents’ perspectives of germline genome sequencing is critical to successful clinical implementation.

Methods

A total of 182 parents of 144 children (<18 years of age) with poor-prognosis cancers enrolled in the Precision Medicine for Children with Cancer trial completed a questionnaire at enrollment and after the return of their child’s results, including clinically relevant germline findings (received by 13% of parents). Parents’ expectations of germline genome sequencing, return of results preferences, and recall of results received were assessed. Forty-five parents (of 43 children) were interviewed in depth.

Results

At trial enrollment, most parents (63%) believed it was at least “somewhat likely” that their child would receive a clinically relevant germline finding. Almost all expressed a preference to receive a broad range of germline genomic findings, including variants of uncertain significance (88%). Some (29%) inaccurately recalled receiving a clinically relevant germline finding. Qualitatively, parents expressed confusion and uncertainty after the return of their child’s genome sequencing results by their child’s clinician.

Conclusions

Many parents of children with poor-prognosis childhood cancer enrolled in a precision medicine trial expect their child may have an underlying cancer predisposition syndrome. They wish to receive a wide scope of information from germline genome sequencing but may feel confused by the reporting of trial results.     

Intraoperative Radioisotope Injection for Sentinel Lymph Node Biopsy

Background  Preoperative injection of technetium-99 m sulfur colloid (Tc-99) in the Nuclear Medicine Department for localizing sentinel lymph nodes (SLNs) can be extremely painful for the patient. The difficulties in scheduling and the delay in starting surgery can be frustrating for the patient and the surgeon. We hypothesized that intraoperative injection facilitated by the subareolar technique would obviate the problems associated with preoperative injection. Methods  We performed an institutional review board-approved prospective study of patients with operable breast cancer who were candidates for an SLN biopsy from October 2002 to January 2006 at our institution. After induction of general anesthesia, patients underwent a subareolar injection of 1 mCi Tc-99 unfiltered and blue dye. Data comparing preoperative cost were collected. Results  A total of 236 patients had 252 intraoperative SLN procedures. The mean patient age was 57.3 (range, 24-88) years. The mean ± standard deviation time from injection to incision was 25.5 ± 16.2 minutes. Identification rate was 96%, and the number of SLNs identified per patient was 1.6 ± .8. The count of SLN was 60,313 ± 134,692 with 20% SLN positivity. Tumor staging distribution was standard staging terminology for an in situ cancer (Tis) = 17 with 0% (+) SLN, T1 = 115 with 11% (+) SLN, T2 = 56 with 29% (+) SLN, T3 = 19 with 37% (+) SLN, and T4 = 4 with 50% (+) SLN. Maximum exposure to the surgeon was well below maximum, at 100 μSV/mo. Preoperative injection had an additive charge of $1325 associated with it for imaging, injection, and interpretation of images by physician. Conclusion  Intraoperative subareolar injection of Tc-99 localizes the SLN and avoids the pain, vasovagal events, delays, and cost associated with preoperative procedure.     

TNFA-308G>A polymorphism influences the TNF-alpha response to altered vaginal flora

OBJECTIVE: To investigate the association between a tumor necrosis factor-alpha (TNF-alpha) gene polymorphism, vaginal TNF-alpha level, and microbial flora in pregnant women. METHODS: Vaginal samples from 203 women at 18-22 weeks' gestation were analyzed for microflora. TNFA-308G>A polymorphism was analyzed by polymerase chain reaction and restriction endonuclease analysis and TNF-alpha concentration was determined by ELISA. Outcome data were subsequently obtained. RESULTS: The vaginal TNF-alpha concentration was elevated in TNFA-308A carriers only in the presence of abnormal vaginal flora. A median TNF-alpha level of 10.94 pg/ml in TNFA-308A carriers with bacterial vaginosis (BV) was significantly higher than that of 1.77 pg/ml in TNFA-308A carriers without BV (P=.02), and 1.72 pg/ml in TNF-308G homozygotes with BV (P=.01). CONCLUSION: The TNFA-308G>A polymorphism influences the local TNF-alpha response to altered vaginal microflora. This suggests that the nature of the host response to microbial invasion in the lower female genital is genetically determined.     

A COMPARISON OF CORNEAL ENDOTHELIAL MORPHOLOGY IN CORNEA GUTTATA, FUCHS' DYSTROPHY AND BULLOUS KERATOPATHY

Changes on corneal endothelial specular microscopy were compared in 14 patients with cornea guttata, 4 patients with Fuchs' corneal dystrophy and 19 patients with various forms of bullous keratopathy. The patients with cornea guttata showed well marked guttae 1 to 6 endothelial cells in diameter in the endothelial mosaic and in the relief mode while the endothelial mosaic was usually otherwise within normal limits. In 2 patients with Fuchs' dystrophy the endothelium could be examined, showing gross guttae but a few areas of relatively normal endothelial cells. The unaffected eye of 3 other patients snowed findings similar to cornea guttata, but with some reduction in endothelial cell count in 2 patients. The patients with bullous keratopathy fell into 2 groups, one with gross reduction in cell count in a markedly abnormal endothelial cell mosaic, the other a mixed group with moderate reduction in cell count and numerous guttae. Some miscellaneous cases included one of aphakic peripheral bullous keratopathy, one associated with cyclitis and aphakia and 2 with idiopathic non-surgical bullous keratopathy. We believe the corneal endothelium is not grossly abnormal away from the guttae in Fuchs' dystrophy, but the gross guttata formation determines the endothelial dysfunction.