Addressing high cervical cancer rates in the Rio Grande Valley along the Texas-Mexico border: a community-based initiative focused on education, patient navigation, and medical provider training/telementoring.

AIMS: Cervical cancer incidence and mortality rates are approximately 55% higher in the Rio Grande Valley (RGV) along the Texas-Mexico border compared with the average rates in the US. Our aim was to improve cervical cancer prevention efforts in the RGV through a comprehensive multilevel intervention initiative focused on community education, patient navigation, and training of local providers. METHODS: We initiated a program in the RGV which consisted of (1) community education, (2) patient navigation, and (3) a training/mentoring program for local medical providers including hands-on training courses coupled with telementoring using Project ECHO® (Extension for Community Health Outcomes). We assessed the number of women undergoing cervical cancer screening, diagnosis, and treatment at three participating clinics caring for underserved women in the region. RESULTS: From November 2014 to October 2018, 14,846 women underwent cervical cancer screening. A total of 2030 (13.7%) women underwent colposcopy for abnormal results (179% increase over baseline) and 453 women underwent loop electrosurgical excision procedures (LEEPs) for treatment of cervical dysplasia. Invasive cancer was diagnosed in 39 women who were navigated to a gynecologic oncologist for treatment. Seven local medical providers were trained to perform colposcopy and/or LEEP. Project ECHO telementoring videoconferences were held every 2 weeks for a total 101 sessions with an average of 22 participants per session and a total of 180 patient cases presented and discussed. CONCLUSIONS: Our program led to a large number of women undergoing diagnosis and treatment of cervical dysplasia in the RGV. If sustained, we anticipate these efforts will decrease cervical cancer rates in the region. The program is currently being expanded to additional underserved areas of Texas and globally to low- and middle-income countries.

Quality of life after radical trachelectomy for early-stage cervical cancer: A 5-year prospective evaluation.

OBJECTIVES: To longitudinally assess quality of life (QOL) in women undergoing radical trachelectomy for early-stage cervical cancer. METHODS: We prospectively enrolled patients with stage IA1-IB1 cervical cancer prior to undergoing radical trachelectomy to complete validated QOL instruments. These instruments included the General Health-Related QOL (SF-12), Functional Assessment of Cancer Therapy-Cervix (FACT-Cx), MD Anderson Symptom Inventory (MDASI), Female Sexual Functioning Index (FSFI), and Satisfaction with Decision scale (SWD). Instruments were filled out at baseline, postoperatively at 6weeks, 6months, 1year, and annually thereafter for 4years. RESULTS: Thirty-nine patients enrolled in the study, and 32 patients were evaluable. The scores for FSFI-arousal (p=0.0002), lubrication (p<0.0001), orgasm (p=0.006), pain (p=0.01), satisfaction (p=0.03) and total score (p=0.004) showed a significant decline at 6weeks then returned to baseline levels by 6 months. The scores for FACT-Cx functional well-being (p=0.02) and physical well-being (p<0.0001), SF-12 bodily pain (p<0.0001), physical functioning (p<0.0001), role physical (p<0.0001), role emotional (p=0.03), social functioning (p=0.002), and MDASI total (p=0.04) showed significantly worsened symptoms at 6weeks then returned to baseline by 6months. The scores for FACT-Cx emotional well-being showed significant worsening of symptoms that persisted at 6-weeks (p=0.004), 6months (p=0.007), 1year (p=0.001), 2years (p=0.002), and 4 years (p=0.03). There was no difference in SWD. CONCLUSIONS: Several quality of life assessments decline immediately postoperatively after radical trachelectomy, however, return to baseline thereafter. The long-term emotional impact of this surgery highlights a need for perioperative counseling in these patients.

Is MRI helpful in assessing the distance of the tumour from the internal os in patients with cervical cancer below FIGO Stage IB2?

AIM: To determine the ability of magnetic resonance imaging (MRI) in detecting tumour-free margins from the internal os (IO). MATERIALS AND METHODS: A database search yielded 79 women with early-stage cervical cancer who underwent radical hysterectomy and preoperative MRI. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of MRI in assessment of ≤5 and >5 mm IO involvement were calculated with histopathological surgical specimen findings considered to be the reference standard. A main and subset analysis was performed. The subset analysis included only those patients who would have been considered for radical trachelectomy. RESULTS: For predicting a distance between the tumour and the IO of ≤5 mm, MRI had a sensitivity of 73%, a specificity of 98.3%, a PPV of 95%, a NPV of 88.1%, and an accuracy of 89.8% for the main analysis, and sensitivity of 81.8%, a specificity of 93.2% a PPV of 69.2% a NPV of 96.5% and an accuracy of 91.4% for the subset analysis. CONCLUSION: MRI has high specificity, NPV, and accuracy in detecting tumour from the IO, making MRI suitable for treatment planning in patients desiring trachelectomy to preserve fertility.

Small cell carcinoma of the ovary-hypercalcemic type (SCCOHT): A review of 47 cases.

OBJECTIVE: Small cell carcinoma of the ovary-hypercalcemic type (SCCOHT) is a rare disease with a poor prognosis. SCCOHT has recently been shown to be associated with SMARCA4 gene mutations as well as molecular and genetic similarities to malignant rhabdoid tumors (MRT). The objective of our study is to describe the clinical characteristics, treatment modalities and outcomes of 47 patients with SCCOHT. METHODS: We performed a retrospective analysis of 47 patients with SCCOHT evaluated at MD Anderson Cancer Center between 1990 and 2014. Medical records were reviewed for demographic information, pathologic findings, treatment regimens and outcomes. RESULTS: Median age at diagnosis was 30 years (range 5-46). All patients underwent surgery with unilateral salpingo-oophorectomy (USO) performed in 26 patients (55%), and hysterectomy with bilateral salpingooophorectomy (BSO) in 21 patients (45%). Sixteen patients (34.0%) had stage I disease, six (12.8%) stage II, 23 (48.9%) stage III, and two patients (4.3%) had stage IV disease. Information on adjuvant treatment was available for 43 patients: 83.3% received chemotherapy alone, 9.5% chemotherapy followed by radiotherapy, 2.4% chemoradiation, and 4.8% did not receive any adjuvant therapy. Median follow-up was 13.2 months (range, 0.1 to 210.7) with a median overall survival of 14.9 months. Multi-agent chemotherapy and radiotherapy were associated with a better prognosis. CONCLUSION: Our findings suggest that aggressive therapy including multi-agent chemotherapy and possibly radiotherapy may extend survival. Further study is needed to improve outcomes in these patients including the adoption of systemic therapies used in MRT as well as the development of novel agents targeting specific mutations.

Optimizing modulation frequency for structured illumination in a fiber-optic microendoscope to image nuclear morphometry in columnar epithelium.

Fiber-optic microendoscopes have shown promise to image the changes in nuclear morphometry that accompany the development of precancerous lesions in tissue with squamous epithelium such as in the oral mucosa and cervix. However, fiber-optic microendoscopy image contrast is limited by out-of-focus light generated by scattering within tissue. The scattering coefficient of tissues with columnar epithelium can be greater than that of squamous epithelium resulting in decreased image quality. To address this challenge, we present a small and portable microendoscope system capable of performing optical sectioning using structured illumination (SI) in real-time. Several optical phantoms were developed and used to quantify the sectioning capabilities of the system. Columnar epithelium from cervical tissue specimens was then imaged ex vivo, and we demonstrate that the addition of SI achieves higher image contrast, enabling visualization of nuclear morphology.

Vulvar intraepithelial neoplasia (VIN 2/3): comparing clinical outcomes and evaluating risk factors for recurrence.

OBJECTIVE: To evaluate demographic and clinical characteristics associated with the development of vulvar intraepithelial neoplasia (VIN 2/3), and factors associated with recurrence. METHODS: A retrospective chart review of 303 patients with VIN 2/3 evaluated at a single institution between 1993 and 2011 was performed. Medical records were reviewed for demographic information, risk factors, treatment type, pathologic diagnosis, and recurrence/outcome information. RESULTS: Median age at diagnosis was 47 years (range 14-87). 40% of patients reported current tobacco use and 26% reported previous use. Primary treatment included excision (n=176, 59%), laser ablation (n=40, 13%), imiquimod (n=22, 7.4%), excision with laser (n=24, 8.1%), excision with imiquimod (n=10, 3.4%), and laser with imiquimod (n=3, 1.0%). 92 patients (62.6%) were noted to have positive margins, which was associated with larger tumor size (p=0.004). 87 patients (28.7%) developed recurrent disease, which was associated with smoking (p<0.001), larger lesion size (p=0.016), and positive margins (p=0.005). On univariate analysis, higher rates of recurrence were associated with laser ablation (45.0%) compared with excision (26%) or imiquimod (13.6%) (p=0.018). However, on multivariate analysis of recurrence-free survival (RFS) these therapies were equivalent when used individually, but the use of excision plus laser had an adverse impact on RFS (p<0.001). 7 patients (2.3%) recurred with invasive disease a median of 109 months (range 12-327) from initial VIN 2/3 diagnosis. CONCLUSIONS: This large cohort of women with VIN 2/3 further delineates the demographic and clinical factors associated with VIN 2/3. High rates of recurrence were noted and found to be associated with smoking, larger lesion size, and positive margins. While higher rates of recurrence were found among those treated with laser ablation, it was not inferior with respect to RFS when used alone, but the use of laser with excision was associated with decreased RFS. Our findings provide hypothesis-generating material for further research in the management of VIN2/3.

Communication of BRCA1 and BRCA2 genetic test results to health care providers following genetic testing at a tertiary care center.

Individuals at high risk for hereditary cancers often receive genetic counseling and testing at tertiary care centers; however, they may receive care for long-term management of their cancer risk in community settings. Communication of genetic test results to health care providers outside of tertiary care settings can facilitate the long-term management of high risk individuals. This study assessed women's communication of BRCA1/BRCA2 genetic test results to health care providers outside of tertiary care settings (termed "outside" health care providers, or OHCPs) and women's perceptions regarding communication of results. Women (n = 312) who underwent BRCA1/BRCA2 genetic counseling and testing completed a questionnaire assessing whether or not they shared test results with OHCPs and perceptions regarding the communication of test results to OHCPs. Most (72%) shared genetic test results with OHCPs. Women with no personal history of cancer were more likely to have shared results compared to women with a personal history of cancer. Mutation status did not significantly predict sharing of genetic information. Most reported positive perceptions regarding the disclosure of genetic test results to OHCPs. The majority did not report any concerns about potential insurance discrimination (88%) and indicated that OHCPs were able to appropriately address their questions (81%). Although most women shared their genetic test results with OHCPs, those with a personal history of cancer may need further encouragement to share this information. Tertiary care centers should facilitate outreach and education with OHCPs in order to assure appropriate long-term cancer risk management for high risk populations.

Recurrence patterns and prognosis of endometrial stromal sarcoma and the potential of tyrosine kinase-inhibiting therapy.

OBJECTIVE: Endometrial stromal sarcoma (ESS) is a rare uterine malignancy. The current treatment approaches yield unsatisfactory results, and potential therapeutic targets need exploration. METHODS: We reviewed the electronic medical records of 74 patients with low-grade ESS who had been evaluated at the University of Texas MD Anderson Cancer Center between 1995 and 2006. Using immunohistochemistry, we tested the expression of targets in paraffin-embedded tissue samples taken from 13 of the patients. RESULTS: Forty-seven patients (64%) had a recurrence, and 16 (22%) had died of their disease at last follow-up. The 10-year progression-free survival (PFS) rate was 43% (median PFS duration, 108months), and the overall survival (OS) rate was 85% (median OS, 288months). Patients who received hormonal therapy had an overall response rate of 27%; another 53% had stable disease, with a median time to progression of 24months. No complete response or partial response was observed among patients who received radiotherapy or chemotherapy. In the paraffin-embedded specimens we tested, c-abl was expressed universally. Expression of PDGF-α, PDGF-ß, VEGF, and c-Kit was detected in 33%, 36%, 54%, and 8%, of specimens, respectively. EGFR and HER-2 were not detectable in any specimens. CONCLUSIONS: Our study suggests that ESS is a hormone-dependent malignancy, with hormonal therapy having activity in recurrent disease. Targeted therapy, specifically targeting c-abl may be a potential treatment for this disease.

Gynecologic cancers associated with Lynch syndrome/HNPCC.

Lynch syndrome/hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant inherited cancer susceptibility syndrome caused by a germline mutation in one of the deoxyribonucleic acid (DNA) mismatch repair genes. It is associated with early onset of cancer (age younger than 50 years) and the development of multiple cancer types, particularly colon and endometrial cancer. Women with Lynch syndrome have a 40-60% risk of endometrial cancer, which equals or exceeds their risk of colorectal cancer. In addition, they have a 12% risk of ovarian cancer. Despite limited information on the efficacy of surveillance in reducing endometrial and ovarian cancer risk in women with Lynch syndrome, the current gynecologic cancer screening guidelines include annual endometrial sampling and transvaginal ultrasonography beginning at age 30-35 years. In addition, risk-reducing surgery consisting of prophylactic hysterectomy and bilateral salpingooophorectomy should be offered to women aged 35 years or older who do not wish to preserve their fertility.

Gynecologic cancers associated with Lynch syndrome/HNPCC

Lynch syndrome/hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant inherited cancer susceptibility syndrome caused by a germline mutation in one of the deoxyribonucleic acid (DNA) mismatch repair genes. It is associated with early onset of cancer (age younger than 50 years) and the development of multiple cancer types, particularly colon and endometrial cancer. Women with Lynch syndrome have a 40-60% risk of endometrial cancer, which equals or exceeds their risk of colorectal cancer. In addition, they have a 12% risk of ovarian cancer. Despite limited information on the efficacy of surveillance in reducing endometrial and ovarian cancer risk in women with Lynch syndrome, the current gynecologic cancer screening guidelines include annual endometrial sampling and transvaginal ultrasonography beginning at age 30-35 years. In addition, risk-reducing surgery consisting of prophylactic hysterectomy and bilateral salpingooophorectomy should be offered to women aged 35 years or older who do not wish to preserve their fertility (AU)

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Primary chemoprevention of endometrial hyperplasia with the peroxisome proliferator-activated receptor gamma agonist rosiglitazone in the PTEN heterozygote murine model.

PTEN mutations have been implicated in the development of endometrial hyperplasia and subsequent cancer. Peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonists have demonstrated antineoplastic and chemopreventive effects. The purpose of this study was to evaluate the effects of the PPAR-gamma agonist rosiglitazone on both PTEN wild type and PTEN null cell lines and in the PTEN heterozygote((+/-)) murine model. Hec-1-A (PTEN wild type) and Ishikawa (PTEN null) cells were treated with rosiglitazone. Thirty-five female PTEN(+/-) mice were genotyped and placed into one of four groups for treatment for 18 weeks: A) PTEN wild type with 4 mg/kg rosiglitazone, B) PTEN(+/-) mice with vehicle, C) PTEN(+/-) mice with 4 mg/kg rosiglitazone, and D) PTEN(+/-) mice with 8 mg/kg rosiglitazone. Proliferation and apoptosis were measured by bromodeoxyuridine (BrdU) and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling of DNA fragmentation sites assay. Rosiglitazone caused cell growth inhibition in both Hec-1-A and Ishikawa in a dose-dependent manner (P < 0.02 and P < 0.03, respectively). Rosiglitazone also induced apoptosis in both Hec-1-A (P < .001) and Ishikawa (P < .001) cells in a dose-dependent manner. In the murine model, rosiglitazone decreased proliferation of the endometrial hyperplastic lesions (B vs C; 39.7% vs 9.3% and B vs D; 39.7% vs 4.2%; P < 0.0001) and increased apoptosis of glandular endometrial epithelial cells (B vs C; 2.8% vs 22.4%; P < 0.0001 and B vs D; 2.8% vs 30.2%; P = 0.003). PPAR-gamma agonist rosiglitazone inhibits proliferation and induces apoptosis in both PTEN intact and PTEN null cancer cell lines and in hyperplastic endometrial lesions in the PTEN(+/)(-)murine model.

Loss of phosphatase and tensin homologue deleted on chromosome 10 and phosphorylation of mammalian target of rapamycin are associated with progesterone refractory endometrial hyperplasia.

The objective of our study was to evaluate the phosphatase and tensin homologue deleted on chromosome 10 (PTEN), p27, and mammalian target of rapamycin (mTOR) expressions in women with progesterone-responsive and refractory endometrial hyperplasia (EH) samples and to determine if these markers could be associated with response or used as potential targets for treatment. Thirty-eight matched pre- and posttreatment pairs of paraffin-embedded endometrial biopsies were obtained from patients with EH. Immunohistochemical analysis for PTEN, p27, and phospho-mTOR were performed on all samples. Median age at diagnosis was 49 years (20-79 years). Median treatment interval was 3 months (1-12 months). Sixteen patients (42.1%) had complete resolution of their hyperplasia (responders), and 22 (57.9%) had persistent hyperplasia (nonresponders) after treatment with progesterone. In the pretreatment samples, no markers were found to predict nonresponders. In posttreatment samples, loss of PTEN expression with phospho-mTOR expression was observed in more nonresponders than responders (40.9% vs 6.3%; P= 0.03). Phospho-mTOR overexpression was found in 63.6% of nonresponders. We found that persistent hyperplasia refractory to progesterone therapy was associated both with the loss of PTEN and with the loss of phosphorylation of mTOR. In select cases of non-responsive progesterone refractory EH, a rational target for treatment may involve the mTOR pathway.

Correlation of cyclin D1 and cyclin D3 overexpression with the loss of PTEN expression in endometrial carcinoma.

Cyclins D1 and D3 play key roles in cell cycle progression. The downregulation of cyclin D3 was associated with phosphatase and tensin homolog deleted on chromosome ten-(PTEN)-induced cell cycle arrest. We attempted to determine whether cyclin D1 and D3 overexpression is correlated with PTEN inactivation in endometrioid endometrial cancer (EEC). The expression of PTEN, cyclin D1, and cyclin D3 were determined by immunohistochemical analysis in 105 EEC specimens. Forty-three percent of the EEC demonstrated loss of PTEN expression. Cyclin D3 was overexpressed in only 18% of the EEC specimens and was not associated with tumor grade. Cyclin D1 was overexpressed in 64% of the specimens and was more common in moderate or high-grade tumors (P = 0.002 and P = 0.02, respectively). The overexpression of cyclin D3 was not correlated with loss of PTEN in the EEC. The overexpression of cyclin D1 was much higher in grade 1 tumors with negative PTEN than tumors with positive PTEN expression (67% vs 26%). The overexpression of cyclin D3 was neither frequent nor correlated with the loss of PTEN expression. The overexpression of cyclin D1 was higher in the low-grade tumors with negative PTEN expression than tumors with positive PTEN expression. Overexpression of cyclin D1 is frequent in moderate or high-grade EECs and likely results from multiple mechanisms.

Double-layer everted saphenous vein patch angioplasty for carotid endarterectomy.

Saphenous vein patch angioplasty is the preferred method of closure of the arteriotomy site during carotid endarterectomies. A major early complication of the saphenous vein patch is rupture of the patch which can occur within the first few postoperative days. The reported incidence varies from 0.5% to 4%. Patch rupture can result in stroke or death. From May 1992 to April 1999, autogenous everted double-layer saphenous vein patch was used in 192 carotid endarterectomies performed on 168 patients; 96 males and 72 females. The age range was from 54 to 94 years with a mean age of 73 years. The saphenous vein is harvested from the ankle. It is everted and then used as a double-layer patch. The follow-up period was from 3 to 74 months, with a mean of 24 months. Postoperatively, there were no patch ruptures or late aneurysm formation. There was no perioperative mortality. Everted double-layer saphenous vein patch eliminates the risk of patch rupture and at the same time retains the benefits of an autologous nonprosthetic graft. Saphenous vein from the ankle can be safely used for carotid angioplasty as a double layer patch.