Denise Uyar

3-T MRI-based adaptive brachytherapy for cervix cancer: Treatment technique and initial clinical outcomes

PURPOSEnTo report the techniques and initial clinical outcomes for MRI-based adaptive brachytherapy (MRIB-ABT) using 3-T MRI.nnnMETHODS AND MATERIALSnAll patients who underwent MRIB-ABT between January 2008 and June 2012 for cervical cancer using 3-T MRI for at least three fractions were retrospectively reviewed. The institutional standard for initiation of brachytherapy planning was 100% of dose at point A and 160% at the vaginal surface with five fractions of 500-550xa0cGy at Point A. The dose distribution was modified to enhance coverage of the high-risk clinical target volume (HR-CTV) and to spare the organs at risk (OAR) by altering dose specification distances around the tandem and the percentage of the Point A dose around the ring or ovoids.nnnRESULTSnEighteen patients (FIGO stages IBxa0=xa04, IIxa0=xa012, IIIxa0=xa01, and IVAxa0=xa01) underwent eighty-two 3-T MRI-based insertions. All patients received 3D conformal, external beam radiation (45-50.4xa0Gy). The median gross tumor volume pretreatment was 38xa0cm(3) (2-165xa0cm(3)) compared with 4.8xa0cm(3) (1-9xa0cm(3)) at the first high-dose rate fraction with a median volume reduction of 88%. Dose specification at the level of Point A was altered in 51% of 3-T MRI fractions from the standard 20xa0mm (range, 14-18xa0mm) and in 8% at the ring surface to optimally cover the HR-CTV and spare the OAR. The 2-year local control, disease-specific survival, and overall survival are 100%, 100%, and 93%, respectively.nnnCONCLUSIONSnMRIB-ABT using 3-T MRI for treatment of cervix cancer allows for customized alterations in dose specification that minimize dose to the OAR and maximize coverage of the HR-CTV.

Apoptotic pathways of epothilone BMS 310705.

OBJECTIVEnBMS 310705 is a novel water-soluble analog of epothilone B currently in phase I clinical evaluation in the treatment of malignancies such as ovarian, renal, bladder, and lung carcinoma. Using an early passage cell culture model derived from the ascites of a patient clinically refractory to platinum/paclitaxel therapy, we evaluated the pathway of caspase-mediated apoptosis.nnnMETHODSnCells were treated for 1 h and subsequently evaluated for apoptosis, survival, and caspase activity. Apoptosis was determined by fluorescent microscopy. Caspase-3, -8, and -9 activities were determined by fluorometry using target tetrapeptide substrates. Mitochondrial release of cytochrome c was determined by immunoblot analysis.nnnRESULTSnAfter treatment with BMS 310705, apoptosis was confirmed in >25% of cells at 24 h. Survival was significantly lower (P < 0.02) in cells treated with 0.05 micro M BMS 310705 vs paclitaxel. Analysis revealed an increase of caspase-9 and -3 activity; no caspase -8 activity was observed. Release of cytochrome c was detected at 12 h following treatment. SN-38 and topotecan failed to induce apoptosis.nnnCONCLUSIONSnBMS 310705 induces significant apoptosis, decreases survival, and utilizes the mitochondrial-mediated pathway for apoptosis in this model.

Positive predictive value of liquid-based and conventional cervical Papanicolaou smears reported as malignant

OBJECTIVESnThe predictive value of cervical Papanicolaou (Pap) smears reported as positive for malignancy, especially those obtained by the liquid-based method, has not been adequately assessed. The objectives of this study are to determine the positive predictive value of Papanicolaou smears with features of malignancy, to compare the accuracy of Papanicolaou smears obtained by the liquid-based method to those obtained by the conventional technique in this setting, and to study the factors influencing a false-positive cytologic diagnosis of malignancy.nnnMATERIALS AND METHODSnPap smears significant for malignant cytology were identified at Fletcher Allen Health Care Hospital in Burlington, VT, from May 1, 1995, to April 30, 2001. A retrospective review of the hospital records and pathology reports was performed documenting patient characteristics, the collection technique, and the final histology. An independent review of the cytology and histology was performed. The positive predictive value and false-positive rate of malignant cytology were calculated for the liquid-based and conventional Pap smear techniques.nnnRESULTSnA total of 472,743 Pap smears were performed during the period specified. One hundred four Pap smears were reported as positive for malignancy, yielding a prevalence rate of 0.02%. A total of 68 patients had paired cytology and histology specimens. Malignant cytology was identified in 36 smears obtained by the liquid-based technique and 32 smears obtained by the conventional technique. A true-positive result, meaning malignant cytology confirmed by the presence of invasive carcinoma on histology, was obtained in 61 of 68 (89.7%) patients. A false-positive result, meaning malignant cytology not confirmed by histology, was obtained in 7 of the 68 (10.3%) patients. The false-positive rate of malignant cytology was 8.4% for the liquid-based technique and 12.5% for the conventional technique. All 7 false-positive smears were diagnosed with high-grade dysplasia by histology. Three of the 7 patients with high-grade dysplasia had previous treatment for dysplasia, one of whom was also pregnant at the time of the smear.nnnCONCLUSIONSnMalignant cervical Papanicolaou smear cytology has a high positive predictive value in the setting of gynecologic and nongynecologic malignancies. Previous treatment for cervical dysplasia or pregnancy may influence the false-positive rate of malignant cytology.

False positive diagnosis in conventional and liquid-based cervical specimens.

OBJECTIVEnTo examine conventional and liquid-based cervical smears falsely diagnosed as malignant at our institution and to investigate, through cytologic-histologic correlation, factors influencing false positive diagnoses.nnnSTUDY DESIGNnCervical cytologic diagnoses of malignancy from May 1, 1995, to April 30, 2001, were retrieved through a computer search. A retrospective review of hospital records and pathology reports was performed. Cases identified as false positives were reviewed and correlated with histologic follow-up specimens.nnnRESULTSnA group of 68 patients with malignancy reported on cervical smears and with histologic follow-up was identified. Conventional smears numbered 32 (47%); the remaining 36 (53%) were liquid-based samples. Of the total, 7 false positive cases (10.3%) were identified in 4 conventional and 3 liquid-based preparations. Cytologic diagnosis in these cases was squamous cell carcinoma in 5 and adenocarcinoma in 2. On histologic follow-up, all 7 patients were ultimately found to have high grade squamous intraepithelial lesions (HSILs) without invasion. Review of the original slides confirmed most, or all, of the following features in all cases: major cellular pleomorphism, extensive cytoplasmic keratinization, intense nuclear pyknosis, background necrosis and severe atrophy.nnnCONCLUSIONnThere was no significant difference in rates of false positive diagnoses between conventional (12.5%) and liquid-based (8.3%) samples. The chief reason for overdiagnosis in this series was the capacity of HSIL to exfoliate cells mimicking invasive malignancy, particularly when keratinized and especially in an atrophic milieu. The other cause of false positivity was superimposition of inflammation and atypical reparative change on a background of HSIL, which then suggested invasion.

Genomics of Cervical Cancer and the Role of Human Papillomavirus Pathobiology

Cervical cancer represents one of the most common malignancies in women worldwide and predominantly affects women of poor socioeconomic status. Persistent infection with high-risk human papillomavirus (HPV)3 is an essential factor for development of cervical cancer. HPV infection is also associated with cancers of the vulva, vagina, anus, and oropharynx. Globally, an estimated 610 000 (4.8%) of the 12.7 million new cancer cases that occurred in 2008 could be attributed to HPV infection, and >500 000 of those cases represent cancers of the cervix alone (1). Within the last 2 decades, research has culminated in major advances in techniques for cervical cancer screening using HPV DNA and has led to a vaccine to prevent HPV infection. Yet, our strategies for the care and treatment of todays patients already infected with HPV need urgent attention. Women diagnosed with invasive and metastatic cervical cancer are in critical need of more-sophisticated prognostic markers, targeted therapeutic options, and more-accurate surveillance strategies.nnThere are about 120 HPV types, and types 16 and 18 are associated with 70% of the cases of cervical cancer worldwide. Many studies have shown that HPV-18–associated cervical cancer is a strong independent prognostic factor for poorer disease-free survival for women undergoing surgery or radiation for early-stage invasive cervical cancer (2). The biology behind the poorer outcomes is unknown, but studies have suggested that sequence variation in HPV genes produces differences in their oncogenic potential. For example, HPV-18 E6 4 (E6 transforming protein) oncogene variants differentially regulate members of the Akt/P13K pathway and show increased expression of genes involved in cancer cell extravasation and metastasis (3, 4).nnHPV integration into the host genome is a critical step in cervical carcinogenesis and is found in almost all invasive cervical cancers. Integration frequently disrupts HPV E2 (E2 regulatory protein) gene expression, …

A prospective pilot study on the incidence of post-operative lymphedema in women with endometrial cancer

To determine the incidence of lower-extremity lymphedema after surgical therapy including lymphadenectomy in endometrial cancer patients using standardized leg measurements. Also, to determine additional risk factors for the development of lymphedema and to study the effect of lymphedema on ones quality of life. In this prospective cohort study, patients with the diagnosis of endometrial cancer who were to undergo definitive surgical management were evaluated pre-operatively and followed post-operatively over the course of two years. Standardized leg measurements were performed by the same individuals at six time-points. Subjects also completed a standardized quality-of-life survey at each time-point. The incidence of lymphedema in 39 women with endometrial cancer using a standardized leg measurement protocol was 12.8% with lymphedema defined as a 20% increase in post-operative leg measurements. There was no significant association between the development of lymphedema and the number of pelvic or para-aortic lymph nodes removed, medical comorbidities, or surgical approach (p > 0.05). Of the five patients who met criteria for lymphedema, only one had worsening quality-of-life concerns post-operatively on the FACT-En, version 4, survey. This is the first prospective study using standardized leg measurements to calculate the incidence of post-operative lymphedema in endometrial cancer. Medical comorbidities, surgical approach, number of lymph nodes removed, and location of lymph nodes removed did not appear to affect the development of lymphedema in this cohort. A prospective, multicenter trial is needed to confirm these findings and to further assess the impact of lymphedema on ones quality of life.

Phase II study of single-agent cabozantinib in patients with recurrent clear cell ovarian, primary peritoneal or fallopian tube cancer (NRG-GY001)

OBJECTIVEnTo evaluate the efficacy and tolerability of cabozantinib in recurrent clear cell ovarian, primary peritoneal or fallopian tube cancer.nnnMETHODSnPatients with recurrent ovarian, fallopian or primary peritoneal tumors with at least 50% clear cell histomorphology, measurable disease, one or two prior regimens and ECOG performance status 0-2 received cabozantinib 60u202fmg orally once daily continuously, in 4-week cycles until disease progression or unacceptable toxicity. Primary endpoints were progression-free survival (PFS) at six months and complete or partial tumor response (as assessed by RECIST 1.1). Secondary endpoints included toxicity, PFS, and overall survival (OS).nnnRESULTSnOver 19u202fmonths, 13 patients were accrued. Fifty-four percent of patients were ≥60u202fyears of age. Performance statuses of 0 and 1 comprised 8 and 5 patients. No objective tumor responses were seen. Three (23% [95% CI: 5%, 54%]) of 13 patients had PFS ≥6u202fmonths, including one patient who received cabozantinib for 23u202fcycles and was still on treatment as of the data cut-off date. Median PFS and OS were 3.6 and 8.1u202fmonths, respectively. There was one patient with a grade 5 event: a thromboembolic event considered possibly related to study therapy; patients cause of death was determined to be due to disease and protocol treatment. Four other patients had thromboembolic events (two grade 3 and one each grade 1 and grade 2). Other grade 3 or higher events reported in two or more patients were nausea, vomiting, fatigue, dyspnea, and dehydration.nnnCONCLUSIONSnCabozantinib demonstrated minimal activity in the second- and third-line treatments of clear cell ovarian, fallopian tube or primary peritoneal carcinoma.

Multifocal Vulvar Smooth Muscle Tumor with an Unusual Intravascular Growth Pattern and Multiple Local Recurrences in a 10-Year-Old Child: A Diagnostic Dilemma

Smooth muscle tumors of the vulva are rare entities with variable morphologic features and clinical behavior. Our report summarizes the case of a multifocal vulvar smooth muscle tumor of undetermined malignant potential with an unusual intravascular growth pattern and subsequent local recurrence in a 10-year-old girl, the youngest case reported to date, and reviews the specific pathologic findings of that category. Vulvar smooth muscle tumors of undetermined malignant potential represent a diagnostic, prognostic, and therapeutic challenge. The histologic features of this case were predictive of local recurrence, although the significance of the intravascular growth pattern is still uncertain. The relationship of this multifocal, recurrent tumor to the clinical entity, vulvar leiomyomatosis, is unknown at this time.

Regional localization of 56 new human chromosome 18-specific yeast artificial chromosomes.

Fifty-six chromosome 18-specific yeast artificial chromosomes (YAC) were isolated from a human monochromosomal somatic cell hybrid DNA library. Fluorescence in situ hybridization revealed that the clones were evenly distributed throughout the chromosome. The clones, with an average insert size of 250 kb, cover about 18% of the euchromatic part of chromosome 18. Of 90 STS markers tested, 17 were represented in this YAC collection. Together with our previously reported set of unique chromosome 18-specific YACs, we now have available 111 regionally mapped, essentially nonchimeric, clones that provide more than 30% coverage and form a framework for the complete physical map.

Implementation of a quality improvement project for universal genetic testing in women with ovarian cancer

OBJECTIVEnThe National Comprehensive Cancer Network recommends all women with ovarian cancer be offered genetic testing. Despite a decade of endorsement, many oncology practitioners have yet to make this a part of routine practice. Referral to genetic counseling and completion of genetic testing among patients at substantial risk of germline mutations are significantly lacking, adversely affecting patient care and squandering an opportunity to maximize cancer prevention efforts. This project determined the impact and feasibility of implementing a basic model for universal referral to genetic counseling and completion of genetic testing in women with a diagnosis of ovarian cancer in an academic gynecology oncology practice with access to electronic health records (EHRs).nnnMETHODSnPatients diagnosed with ovarian cancer from January 2008 to November 2013 were retrospectively reviewed to determine the baseline referral rate for genetic counseling and testing completion in our practice. Implementation of a process change model combining provider training, patient education, enhanced electronic health record documentation and improved patient appointment scheduling strategies were implemented. We then prospectively collected data on all newly diagnosed ovarian cancer patients that had not already undergone genetic testing presenting from December 1, 2013 to November 30, 2016.nnnRESULTSnGenetic referral rates, genetic counseling and testing completion rates were markedly improved. Pre-implementation our genetic testing rate was 27% and post implementation our testing rate was 82% (p-value≤0.001).nnnCONCLUSIONSnLow cost interventions that target education of both providers and patients regarding the importance of genetic testing along with utilization of the EHR and streamlined patient appointment services can significantly increase rates of genetic testing completion.