Laparoscopic pectopexy for patients with intraabdominal adhesions, lumbar spinal procedures, and other contraindications to sacrocolpopexy: a case series.

Laparoscopic pectopexy is an alternative to sacrocolpopexy utilizing fixation points in the anterior pelvis for vaginal vault suspension; it was originally developed for an obese population. This is a retrospective case series of 7 women who underwent laparoscopic pectopexy at one academic Institution between October 2019 and December 2020. The patients had preoperative vaginal vault prolapse (pelvic organ prolapse quantification system [POP-Q], stage 2 and 3). Pectopexy was performed because of relative contraindications to sacrocolpopexy, including use of antiplatelet therapy, extensive adhesions, and chronic back pain with lumbo-spinal fusion. No intraoperative complications were documented in this cohort. Average blood loss was 32.9 mL. All the patients were discharged home within 24 hours. One patient experienced urinary retention that required release of the retropubic midurethral sling placed at the time of pectopexy. The most recent follow-up examination occurred at an average of 127 days after the procedure. All 7 patients had a resolution of their prolapse (POP-Q ≤1). This case series highlights the application of pectopexy for patients with extensive adhesions, use of antiplatelet therapy and lumbar or sacral spinal surgical history. The complication rates and operative results are comparable with sacrocolpopexy at intermediate-term follow-up in this small case series, indicating that pectopexy may be a promising alternative for patients with relative contraindications to sacrocolpopexy. This is the first report of the application of the technique in North America.

A Novel Treatment for Massive Hemorrhage after Maternal Trauma in Pregnancy.

Background Trauma in pregnancy can lead to life-threatening hemorrhage. Conventional treatments of hemorrhage include medical and surgical management. However, if these measures fail uterine compression is an option to control bleeding. We present a case where this management was employed. Case A patient presented at 36 weeks of gestation with multiple injuries after a motor vehicle collision and experienced disseminated intravascular coagulation (DIC). The use of a Bakri balloon in combination with external compression with Coban, a sterile self-adherent bandage, after delivery temporized her bleeding and allowed her to become stable for further management. Conclusion When other measures fail and a hysterectomy is considered unsafe, the combination of internal and external uterine compression is an option.

Mucinous adenocarcinoma of the endometrium with metastasis to the clitoral glans after pelvic exenteration for radiation resistant vaginal cuff recurrence.

Mucinous adenocarcinoma of the endometrium (MACE) is a rare subtype of endometrial adenocarcinoma that often presents a significant diagnostic challenge due to its variation from the conventional morphologic appearance of endometrioid epithelium. This case report is of a woman who has survived 4 years after pelvic exenteration and subsequent vulvectomy for recurrent MACE.

Ergonomics: making the OR a comfortable place.

INTRODUCTION: The objective of this video is to highlight strategies to improve operating room (OR) ergonomics, which will result in increased surgeon comfort during minimally invasive gynecologic surgery and decreased risk of musculoskeletal injury. METHODS: Work-related musculoskeletal disorders (WMSDs) are prevalent among surgeons, including those who perform minimally invasive gynecologic surgery. WMSDs are repetitive strain injuries that can damage a surgeon's muscles, nerves, and/or joints and commonly affect the neck, back, wrist, and hands. In addition to chronic pain, these injuries can lead to decreased job satisfaction and productivity. RESULTS: This video will discuss general ergonomic principles and demonstrate ergonomic techniques in conventional laparoscopic, vaginal, and robotic surgery. CONCLUSIONS: Minimally invasive gynecologic surgery can be physically taxing on the surgeon. Understanding principles and utilizing techniques of OR ergonomics can minimize these physical demands and result in a long, healthy, and pain-free surgical career.

Simple and effective: transvaginal vesico-vaginal fistula repair with a modified Latzko technique.

INTRODUCTION AND HYPOTHESIS: The incidence of vesico-vaginal fistulas after hysterectomies for benign indications in developed countries is less than one percent. The objective of this video is to demonstrate an easy-to-follow, step-by-step approach to repairing a small, uncomplicated vesico-vaginal fistula transvaginally using a modified Latzko technique. METHODS: In this video, we present a case of a 46-year-old woman who developed a simple, uncomplicated vesico-vaginal fistula after a total abdominal hysterectomy. To correct her fistula, we used a modified Latzko technique, which is a transvaginal approach to vesico-vaginal fistula repair that involves mobilizing the vaginal mucosa around the fistula and then closing the pubo-vesical fascia and vaginal mucosa in layers. RESULTS: The patient had successful surgical correction of her vesico-vaginal fistula without recurrence of the fistula. CONCLUSIONS: For small, uncomplicated vesico-vaginal fistulas, a transvaginal approach has an equivalent success rate to that of other approaches with less invasiveness and faster recovery times. Therefore, it is reasonable to use a modified Latzko technique to help restore the quality of life to women affected by small, uncomplicated vesico-vaginal fistulas.

Vaginal Mesh Removal Outcomes: Eight Years of Experience at an Academic Hospital.

OBJECTIVES: The purpose of this study is to describe the clinical history leading up to and the outcomes after vaginal mesh removal surgery at an academic hospital. METHODS: A retrospective case series of patients who underwent vaginal mesh removal from 2008 to 2015 was conducted. Demographics, clinical history, physical examination, pre- and postoperative symptoms, and number and type of reoperations were abstracted. RESULTS: Between February 2008 and November 2015, 83 patients underwent vaginal mesh removal surgery at our hospital. The median time interval from initial mesh placement to removal was 58 months (range, 0.4-154 months). The most common preoperative symptoms were vaginal pain (n = 52, 62%), dyspareunia (n = 46, 55%), and pelvic pain (n = 42, 50%). Intraoperative complications were infrequent (n = 3, 4%). Of patients presenting for follow-up within 4 to 6 weeks postoperatively, the most common symptoms were urinary incontinence (n = 15, 28%), vaginal pain (n = 7, 13%), buttock pain (n = 5, 9%), and urinary tract infection (n = 5, 9%). There were no identifiable risk factors to predict which patients would have persistent postoperative symptoms or who would require more than 1 mesh removal surgery. After vaginal mesh removal, 29 patients (35%) required 1 or more reoperations, with 3 being the highest number of reoperations per patient. The total number of reoperations was 43, with a total of 63 individual procedures performed. Forty-four percent (n = 28) of the procedures were graft removals, 40% (n = 25) were pelvic organ prolapse surgeries (only native tissue repairs), and 16% (n = 10) were stress incontinence surgeries. More than 1 procedure was performed in 49% (n = 21) of the reoperations. CONCLUSIONS: Vaginal mesh removal surgery is safe; however, some patients require more than 1 procedure, and the risk factors for reoperations are unclear.

Multispectral fluorescence imaging of human ovarian and fallopian tube tissue for early-stage cancer detection.

With early detection, 5-year survival rates for ovarian cancer exceed 90%, yet no effective early screening method exists. Emerging consensus suggests over 50% of the most lethal form of the disease originates in the fallopian tube. Twenty-eight women undergoing oophorectomy or debulking surgery provided informed consent for the use of surgical discard tissue samples for multispectral fluorescence imaging. Using multiple ultraviolet and visible excitation wavelengths and emissions bands, 12 fluorescence and 6 reflectance images of 47 ovarian and 31 fallopian tube tissue samples were recorded. After imaging, each sample was fixed, sectioned, and stained for pathological evaluation. Univariate logistic regression showed cancerous tissue samples had significantly lower intensity than noncancerous tissue for 17 image types. The predictive power of multiple image types was evaluated using multivariate logistic regression (MLR) and quadratic discriminant analysis (QDA). Two MLR models each using two image types had receiver operating characteristic curves with area under the curve exceeding 0.9. QDA determined 56 image type combinations with perfect resubstituting using as few as five image types. Adaption of the system for future in vivo fallopian tube and ovary endoscopic imaging is possible, which may enable sensitive detection of ovarian cancer with no exogenous contrast agents.

Assessment of the Role of Intraoperative Frozen Section in Guiding Surgical Staging for Endometrial Cancer.

OBJECTIVE: The aim of this study was to assess the role of intraoperative frozen section (FS) in guiding decision making for surgical staging of endometrioid endometrial cancer (EC). METHODS: Medical records were collected retrospectively on 112 patients with endometrioid EC, who underwent total hysterectomy and bilateral salpingo-oophorectomy at the University of Arizona Medical Center from January 1, 2010, to December 31, 2014. Only patients with endometrioid adenocarcinoma, grade 1, less than 50% myometrial invasion, and tumor size less than 2 cm determined by intraoperative FS omitted lymphadenectomy; otherwise, surgical staging was performed with lymph node dissection. The FS results were compared with the permanent paraffin sections (PSs) to assess the diagnostic accuracy. RESULTS: The concordance rate of different variables between FS and PS in EC was 100%, 89.3% (100/112), 97.3% (109/112), and 95.5% (107/112), respectively, with respecting to histological subtype, grade, myometrial invasion, and tumor size. Diagnostic accurate rate of combined risk factors deciding surgical staging at the time of FS was 95.5% (107/112), and the discordance rate of all risk factors considered between FS and PS was 4.5%, resulting 3 cases (2.7%) undertreated and 2 cases (1.8%) overtreated. CONCLUSIONS: Despite nonideal FS evaluation, intraoperative FS diagnosis for EC is highly reliable by providing guidance for the intraoperative decisions of surgical staging at our institution, and such guidelines may be referenced by the institutions with sufficient gynecologic pathology expertise.

Pilot Clinical Evaluation of a Confocal Microlaparoscope for Ovarian Cancer Detection.

OBJECTIVE: The aim of this study is to evaluate the performance of a confocal fluorescence microlaparoscope for in vivo detection of ovarian cancer. METHODS/MATERIALS: Seventy-one patients scheduled for open or laparoscopic oophorectomy were consented for the imaging study. High-resolution confocal microlaparoscopic images of the epithelial surface of the ovary were acquired in vivo or ex vivo after tissue staining using acridine orange. Standard histologic evaluation of extracted tissue samples was performed and used as the gold standard of disease diagnosis. Trained human observers from different specialties viewed the microlaparoscopic images, rating each image on a 6-point scale ranging from "definitely not cancer" to "definitely cancer." Receiver operating characteristic curves were generated using these scores and the gold standard histopathologic diagnosis. Area under the receiver operating characteristic curve (AUC) was calculated as a performance metric. RESULTS: Forty-five of the consented patients were used in the final evaluation study. From these 45 patients, 63 tissue locations or samples were identified and imaged with the confocal microlaparoscope. Twenty of the samples were high-grade cancers, and the remaining 43 samples were normal or noncancerous. Twenty-three of the samples were imaged in vivo, and the remaining 40 samples were imaged ex vivo. The average AUC score and standard error (SE) for detection of cancer in all images were 0.88 and 0.02, respectively. An independent-samples t test was conducted to compare AUC scores for in vivo and ex vivo conditions. No statistically significant difference in the AUC score for in vivo (AUC, 0.850; SE, 0.049) and ex vivo (AUC, 0.888; SE, 0.027) conditions was observed, t(6) = 1.318, P = 0.2355. CONCLUSIONS: Area under the receiver operating characteristic curve scores indicate that high-resolution in vivo images obtained by the confocal laparoscope can distinguish between normal and malignant ovarian surface epithelium. In addition, in vivo performance is similar to that which can be obtained from ex vivo tissue.

Confocal microlaparoscope for imaging the fallopian tube.

Recent evidence suggests that ovarian cancer can originate in the fallopian tube. Unlike many other cancers, poor access to the ovary and fallopian tubes has limited the ability to study the progression of this deadly disease and to diagnosis it during the early stage when it is most amenable to therapy. A rigid confocal microlaparoscope system designed to image the epithelial surface of the ovary in vivo was previously reported. A new confocal microlaparoscope with an articulating distal tip has been developed to enable in vivo access to human fallopian tubes. The new microlaparoscope is compatible with 5-mm trocars and includes a 2.2-mm-diameter articulating distal tip consisting of a bare fiber bundle and an automated dye delivery system for fluorescence confocal imaging. This small articulating device should enable the confocal microlaparoscope to image early stage ovarian cancer arising inside the fallopian tube. Ex vivo images of animal tissue and human fallopian tube using the new articulating device are presented along with in vivo imaging results using the rigid confocal microlaparoscope system.

IMP3 as a cytoplasmic biomarker for early serous tubal carcinogenesis.

BACKGROUND: Serous tubal intraepithelial carcinoma (STIC) and the p53 signature in tubal mucosa have been supported to be precursor lesions in high-grade serous carcinoma (HGSC) of the fallopian tube, ovary, and peritoneum. It remains critical to find biomarkers for precursor lesions in order to detect HGSCs efficiently. IMP3 is an oncoprotein that has been explored in human malignancies. No studies have specifically addressed the expression of IMP3 in precursor or early lesions of HGSC. The main purposes of this study are to evaluate if IMP3 plays any role in the process of pelvic serous carcinogenesis by examining its expression in HGSC precursor lesions, to examine the relationship between IMP3 and p53 in those precursor lesions, and to check if IMP3 can be used as a biomarker for early diagnosis. METHODS: Immunohistochemistry for IMP3 and p53 was performed and evaluated in 48 HGSCs with STIC, 62 HGSCs without STIC, and 60 benign cases as negative controls. Sections of fallopian tubes with or without STIC , as well as cancers within the ovaries, were studied. IMP3 signature was defined as strong IMP3 cytoplasmic staining in 10 or more consecutive benign-looking tubal epithelial cells. The relationship between IMP3 and p53 overexpression was examined. RESULTS: In the 48 HGSC patients with STIC, IMP3 was positive in 46% of STIC lesions and had a similar positive rate in the invasive components of HGSC. IMP3 was also expressed in normal appearing tubal epithelia (IMP3 signature) in 15 (31%) of 48 HGSC cases with STIC and 10 (16%) of 62 cases without STIC. In contrast, no single IMP3 signature was found in the benign control group. Concordant expression of IMP3 and p53 signatures in the STIC group was found in up to one-third of the cases. There were also five (10%) STIC cases with positive IMP3 and negative p53. CONCLUSIONS: We conclude that IMP3 may be involved in the process and progression of pelvic HGSC and may serve as a complimentary biomarker in diagnosing STIC.

Simultaneous multiplane imaging of human ovarian cancer by volume holographic imaging.

Ovarian cancer is the most deadly gynecologic cancer, a fact which is attributable to poor early detection and survival once the disease has reached advanced stages. Intraoperative laparoscopic volume holographic imaging has the potential to provide simultaneous visualization of surface and subsurface structures in ovarian tissues for improved assessment of developing ovarian cancer. In this ex vivo ovarian tissue study, we assembled a benchtop volume holographic imaging system (VHIS) to characterize the microarchitecture of 78 normal and 40 abnormal tissue specimens derived from ovarian, fallopian tube, uterine, and peritoneal tissues, collected from 26 patients aged 22 to 73 undergoing bilateral salpingo-oophorectomy, hysterectomy with bilateral salpingo-oophorectomy, or abdominal cytoreductive surgery. All tissues were successfully imaged with the VHIS in both reflectance- and fluorescence-modes revealing morphological features which can be used to distinguish between normal, benign abnormalities, and cancerous tissues. We present the development and successful application of VHIS for imaging human ovarian tissue. Comparison of VHIS images with corresponding histopathology allowed for qualitatively distinguishing microstructural features unique to the studied tissue type and disease state. These results motivate the development of a laparoscopic VHIS for evaluating the surface and subsurface morphological alterations in ovarian cancer pathogenesis.

Neurovascular quantitative study of the uterosacral ligament related to nerve-sparing radical hysterectomy.

OBJECTIVE: To analyze the distribution of autonomic nerves and blood and lymphatic vessels in the uterosacral ligament, elucidate detailed anatomy at a surgical level and provide pathobiological evidence for improvement of nerve-sparing radical hysterectomy. STUDY DESIGN: Surgical samples were collected from 15 patients who underwent radical hysterectomy for early stage cervical cancer (FIGO Ib1-IIa). Twenty-nine fresh specimens were divided into cervical, intermediate and sacral sections, and then subdivided into superficial and deep portions from the middle: the medial surface and lateral surface were also subdivided in order to analyze lymphatic vessels. The numbers of nerve branches in each section or portion of the section were analyzed. The lengths of the uterosacral ligaments were measured and immunohistochemistry staining was studied. Autonomic nerves, blood vessels and lymphatic vessels were quantitatively analyzed using image analysis software and biological stereology. RESULTS: The volume density of sympathetic nerves in the deep portion was significantly higher than in the superficial portion (p<0.05), and the number of nerves was greatest in the cervical section (p<0.05). The volume density of blood vessels was not significantly different between the two portions (p>0.05) or among the three sections (p>0.05), and the volume density of the lymphatic vessels was greater in the medial surface (p<0.05), with most of them in the cervical section (p<0.05). CONCLUSIONS: Our study provides systematic mapping of the location and distribution of autonomic nerve branches, blood vessels and lymphatic vessels in the uterosacral ligament.

Secretory cell expansion with aging: risk for pelvic serous carcinogenesis.

OBJECTIVE: Recent advances suggest that precancerous lesions of pelvic serous carcinoma (PSC) originate from tubal secretory cells. The purpose of our study was to determine if increased number of secretory cells shows difference in age and location and to examine their association with serous neoplasia. MATERIALS AND METHODS: Three groups (benign control, high-risk, and PSC) of patients with matched ages were studied. The age data was stratified into 10-year intervals ranging from age 20 to older than 80. The number of secretory and ciliated cells from both tubal fimbria and ampulla segments was counted by microscopy and immunohistochemical staining methods. The data was analyzed by standard contingency table and Poisson distribution methods after age justification. RESULTS: We found that the absolute number of tubal secretory cells increased significantly with age within each age group. Age remained a significant risk factor for serous neoplasia after age adjustment. In addition, a dramatic increase of secretory cells was observed in high-risk and PSC patients. Further, secretory cell expansion (SCE) was more prevalent than secretory cell outgrowth in both fimbria and ampulla tubal segments and was significantly associated with serous neoplasia (p<0.001). CONCLUSIONS: These findings suggest that SCE could potentially serve as a sensitive biomarker for early serous carcinogenesis within the fallopian tube. Findings support a relationship between serous neoplasia and increased secretory to ciliated cell ratios. Findings also support a relationship between frequency of SCE and increasing age, presence of high-risk factors and co-existing serous cancers.

Lynch syndrome related endometrial cancer: clinical significance beyond the endometrium.

Lynch syndrome (LS), an autosomal dominant inherited cancer susceptibility syndrome, also known as hereditary non-polyposis colon cancer (HNPCC), is caused by a germline mutation in one of several DNA mismatch repair (MMR) genes. LS is the most common presentation of hereditary colorectal cancer (CRC), accounting for about 2-5% of all CRC cases. More recently, it is found that a similar number of endometrial cancers is also due to one of the MMR gene mutations. There has been significant progress in LS-related CRC in terms of molecular pathogenesis, risks, genetic basis, and cancer prevention. In contrast, the advance about LS-related endometrial cancer (EC) is very much limited. In this commentary, we summarize the main clinicopathologic features of LS-related EC and propose universal screening for LS in individuals with endometrial cancer.

Wide-field spectral imaging of human ovary autofluorescence and oncologic diagnosis via previously collected probe data.

With no sufficient screening test for ovarian cancer, a method to evaluate the ovarian disease state quickly and nondestructively is needed. The authors have applied a wide-field spectral imager to freshly resected ovaries of 30 human patients in a study believed to be the first of its magnitude. Endogenous fluorescence was excited with 365-nm light and imaged in eight emission bands collectively covering the 400- to 640-nm range. Linear discriminant analysis was used to classify all image pixels and generate diagnostic maps of the ovaries. Training the classifier with previously collected single-point autofluorescence measurements of a spectroscopic probe enabled this novel classification. The process by which probe-collected spectra were transformed for comparison with imager spectra is described. Sensitivity of 100% and specificity of 51% were obtained in classifying normal and cancerous ovaries using autofluorescence data alone. Specificity increased to 69% when autofluorescence data were divided by green reflectance data to correct for spatial variation in tissue absorption properties. Benign neoplasm ovaries were also found to classify as nonmalignant using the same algorithm. Although applied ex vivo, the method described here appears useful for quick assessment of cancer presence in the human ovary.

Phase I trial of intraperitoneal pemetrexed, cisplatin, and paclitaxel in optimally debulked ovarian cancer.

PURPOSE: This phase I trial evaluated intraperitoneal (i.p.) pemetrexed, cisplatin, and paclitaxel in optimally debulked ovarian cancer. EXPERIMENTAL DESIGN: Dose escalation of day 1 i.p. pemetrexed accrued three patients to each of five dose levels (60-1,000 mg/m(2)), along with day 2 i.p. cisplatin (75 mg/m(2)) and day 8 i.p. paclitaxel (60 mg/m(2)). The goals were to determine maximum tolerated dose (MTD), 18-month progression-free survival (PFS), and pharmacokinetics of i.p. pemetrexed. RESULTS: Cycles, given every 21 days, had an 80% 6-cycle completion rate. There was minimal grade III toxicity in the first 4 dose levels and remarkably an almost complete absence of peripheral neuropathy and alopecia. At the highest dose level, two of three patients experienced ≥ grade III and dose-limiting toxicity (DLT; hematologic, infection, gastrointestinal). There was a pharmacokinetic advantage for i.p. pemetrexed with an intraperitoneal:plasma area under the concentration-time curve ratio of 13-fold. Neither analysis of pharmacokinetic nor homocysteine levels explains the unexpected severity of toxicity in those two patients. On the basis of plasma C(24h) levels, the 42 cycles at ≥ 500 mg/m(2) i.p. pemetrexed without DLT, the MTD appears to be 500 mg/m(2). Median PFS is 30.1 months; 18-month PFS is 78.6% (median follow-up 22.4 months). CONCLUSIONS: This i.p.-only regimen in front-line ovarian cancer is feasible with PFS in line with recent literature. We suggest phase II trials of this regimen in this population with i.p. pemetrexed at 500 mg/m(2). The favorable toxicity profile at doses <1,000 mg/m(2), which needs to be confirmed, appears to compare well with standard combination i.v./i.p. platinum/taxane chemotherapy in this disease.

Serous endometrial intraepithelial carcinoma arising in adenomyosis: a report of 5 cases.

Serous endometrial intraepithelial carcinoma (serous EIC) arising in adenomyosis is rare. It may be underrecognized because of its deceiving morphology when embedded in the foci of adenomyosis. Although there is no connection to peritoneal cavity, some cases may be associated with extrauterine disease. It is currently unknown what the etiology for such a disease is. More studies are in need to elucidate the pathogenesis of such a grave malady. We report a series of 5 cases of serous EIC, which may arise in adenomyosis. The 5 cases are in 5 different patients or whom on histopathological examination of their hysterectomy specimens, the finding of adenomyosis involved with serous intraepithelial neoplasia was identified. The finding of interest was the presence of multifoci of adenomyosis; some of those foci were involved in serous EIC. In addition to EIC, lesions of endometrial glandular dysplasia were present in the foci of adenomyosis. To rule out the possibility of endometrial serous carcinoma (ESC) invading into the areas of the adenomyosis, all of the 5 uteri were extensively examined. Among the 5 uteri, the eutopic endometirum showed 1 invasive ESC, 2 serous EIC, and 2 benign resting endometrium without any cancer or precancerous lesions. In 1 uterus with ESC, we did not see any direct spatial connection between the invasive component of ESC and the areas of EIC in the foci of adenomyosis. In 2 uteri with serous EIC within the endometrial cavity, there was a distance of at least 0.5 cm between the lesions within the endometrial cavity and the serous EIC in adenomyosis. The remaining 2 uteri showed no evidence of endometrial malignancy in the endometrial cavity, whereas serous EIC was present only in areas of adenomyosis. Clinicopathologic data including characterized immunohistochemical stainings and p53 gene sequence analysis are presented and clinical significance is discussed.

Overexpression of tumor vascular endothelial growth factor A may portend an increased likelihood of progression in a phase II trial of bevacizumab and erlotinib in resistant ovarian cancer.

PURPOSE: This phase II trial evaluated bevacizumab plus erlotinib in platinum-resistant ovarian cancer; exploratory biomarker analyses, including that of tumor vascular endothelial growth factor A (VEGF-A), were also done. EXPERIMENTAL DESIGN: Forty heavily pretreated patients received erlotinib (150 mg/d orally) and bevacizumab (10 mg/kg i.v.) every 2 weeks until disease progression. Primary end points were objective response rate and response duration; secondary end points included progression-free survival (PFS), toxicity, and correlations between angiogenic protein levels, toxicity, and efficacy. RESULTS: Grade 3 toxicities included skin rash (n = 6), diarrhea (n = 5), fatigue (n = 4), and hypertension (n = 3). Grade 4 toxicities were myocardial infarction (n = 1) and nasal septal perforation (n = 1). Only one grade 3 fistula and one grade 2 bowel perforation were observed. Nine (23.1%) of 39 evaluable patients had a response (median duration, 36.1+ weeks; one complete response), and 10 (25.6%) patients achieved stable disease, for a disease control rate of 49%. Median PFS was 4 months, and 6-month PFS was 30.8%. Biomarker analyses identified an association between tumor cell VEGF-A expression and progression (P = 0.03); for every 100-unit increase in the VEGF-A score, there was a 3.7-fold increase in the odds of progression (95% confidence interval, 1.1-16.6). CONCLUSIONS: Bevacizumab plus erlotinib in heavily pretreated ovarian cancer patients was clinically active and well tolerated. Erlotinib did not seem to contribute to efficacy. Our study raises the intriguing possibility that high levels of tumor cell VEGF-A, capable of both autocrine and paracrine interactions, are associated with resistance to bevacizumab, emphasizing the complexity of the tumor microenvironment.