John B. Liao

Vaginal cuff dehiscence after robotic total laparoscopic hysterectomy.

BACKGROUND: Vaginal cuff dehiscence with small bowel evisceration after hysterectomy is a rare event that may be occurring more frequently with the advent of robotic laparoscopic hysterectomies. CASES: Two women underwent robotic total laparoscopic hysterectomy for menorrhagia and stage I endocervical adenocarcinoma, respectively. Each presented 7–8 weeks postoperatively with abdominal pain and vaginal pressure after intercourse. The small bowel protruded into the vagina through the dehisced vaginal cuff. Both cuffs were repaired vaginally with delayed absorbable suture. One repair required revision 7 weeks after the initial repair. CONCLUSION: Robotic total laparoscopic hysterectomy may be associated with increased risk of vaginal cuff dehiscence and small bowel evisceration. This observation may be because of thermal spread and cuff tissue damage from electrosurgery used for colpotomy.

Human papillomaviruses and cervical cancer.

Carcinoma of the uterine cervix, a leading cause of cancer death in women worldwide, is initiated by infection with high-risk types of human papillomaviruses (HPVs). This review summarizes laboratory studies over the past 20 years that have elucidated the major features of the HPV life cycle, identified the functions of the viral proteins, and clarified the consequences of HPV infection for their host cells. This information has allowed the development of various strategies to prevent or treat infections, including prophylactic vaccination with virus-like particles, therapeutic vaccination against viral proteins expressed in cancer cells, and antiviral approaches to inhibit virus replication, spread, or pathogenesis. These strategies have the potential to cause a dramatic reduction in the incidence of cervical carcinoma and serve as the prototype for comprehensive efforts to combat virus-induced tumors.

Clinical predictors of bevacizumab-associated gastrointestinal perforation.

OBJECTIVES Bevacizumab is a generally well-tolerated drug, but bevacizumab-associated gastrointestinal perforations (BAP) occur in 0 to 15% of patients with ovarian carcinoma. Our goal was to evaluate the clinical predictors of BAP in order to identify factors, which may preclude patients from receiving treatment. METHODS We conducted a review of patients with recurrent epithelial ovarian carcinoma treated with bevacizumab between 2006 and 2009. Demographic and treatment data were collected for statistical analysis. RESULTS Eighty-two patients were identified; perforation occurred in 8 (9.76%). Among patients with perforation, a significantly higher incidence of prior bowel surgeries (p=0.0008) and prior bowel obstruction or ileus (p<0.0001) were found compared to non-perforated patients. The median age at onset of bevacizumab in the perforated group was 3 years younger (60 vs. 63 years, p=0.61). The incidence of thromboembolic events, GI comorbidities, number of prior chemotherapies, and body mass index were similar between the groups. None of the patients in the perforated group developed grade 3 or 4 hypertension, compared to a 32.4% incidence among the non-perforated patients (p=0.09). Upon multivariate analysis, when controlled for age greater or less than 60, prior bowel surgery, obstruction/ileus, and grade 3 or 4 hypertension, only the presence of obstruction/ileus was noted to be a significant predictor of perforation (p=0.04). CONCLUSIONS Predicting BAP remains a challenge. Bowel obstruction or ileus appears to be associated with increased risk of BAP.

The emergence of immunomodulation: combinatorial immunochemotherapy opportunities for the next decade.

In the past decade we have witnessed important advances in the treatment of gynecological cancers and have recognized their potential immunogenicity. This has opened the door to explore immune therapy not only in HPV-induced cancers but also in ovarian and endometrial cancers. Here we will review the off-target immune effects of select chemotherapy drugs commonly used to treat gynecologic cancers and novel tools that can stimulate both the adaptive and innate immune mechanisms such as novel pleiotropic cytokines, Toll-like receptors, and powerful antibodies that can target inhibitory checkpoints, thereby activating effector cellular immune mechanisms and neutralizing suppressor cells. We will also review how existing drugs can be used for combinatorial tumor therapy.

Single-Dose, Therapeutic Vaccination of Mice with Vesicular Stomatitis Virus Expressing Human Papillomavirus Type 16 E7 Protein

ABSTRACT We are developing recombinant attenuated vesicular stomatitis virus (VSV) as a vaccine vector to generate humoral and cell-mediated immune responses. Here, we explore the use of VSV vaccines for cancer immunotherapy. Immunotherapy targeting high-risk human papillomavirus (HPV) lesions has the potential to benefit HPV-infected individuals and cervical cancer patients by generating cytotoxic T cells that kill tumor cells that express viral antigens. A single dose of VSV expressing the HPV type 16 (HPV16) E7 oncogene was used for therapeutic vaccination of mice bearing TC-1 syngeneic tumors, which express HPV16 E7. HPV16 E7-specific T cells were generated and displayed cytotoxic activity against the tumor cells. By 14 days postvaccination, average tumor volumes were 10-fold less in the vaccinated group than in mice that received the empty-vector VSV, and regression of preexisting tumors occurred in some cases. This antitumor effect was CD8 T-cell dependent. Our results demonstrate antitumor responses to HPV16 E7 and suggest that recombinant-VSV-based vaccination should be explored as a therapeutic strategy for cervical carcinoma and other HPV-associated cancers.

Vaginal intraepithelial neoplasia (VAIN) after radiation therapy for gynecologic malignancies: A clinically recalcitrant entity

OBJECTIVES Vaginal dysplasia is associated with prior radiation therapy (RT) for gynecologic malignancies. We reviewed our institutions experience with VAIN in patients who were treated with radiation therapy for a gynecologic malignancy. METHODS A retrospective review of patients treated for VAIN was performed. All cases of patients followed and treated for VAIN after radiation therapy were identified (n=10), along with a cohort of patients with VAIN who did not have radiation therapy (n=23). RESULTS Mean follow-up after initial diagnosis of VAIN was 37.6 months (range: 12 to 72). Cytologic screening events after diagnosis of VAIN (n=105) showed that patients with prior RT were more than twice as likely to have recurrent dysplasia (OR 3.625, 95% CI=from 1.454 to 9.0376) after treatment. Of patients who recurred, the mean time to first recurrence was 12.3 months in cases and 15.3 months in controls, which was not statistically significant (p=0.31). Screening practices at our institution ranged from 3 month to 12 month intervals. 3 patients in the RT group and 1 patient in the control group developed invasive squamous cell cancer of the vagina. CONCLUSIONS Vaginal dysplasia after radiation therapy is more refractory to treatment than dysplasia not associated with radiation therapy, more likely to recur after surgical and ablative therapy, and may also be more likely to progress to invasive cancer. These data support the need for further study to determine the optimal follow-up screening interval and whether aggressive surgical or ablative treatment stems disease progression in this clinical scenario.

Detection of the HE4 protein in urine as a biomarker for ovarian neoplasms: Clinical correlates

OBJECTIVES To measure HE4 levels in urine from normal donors, patients with LMP tumors and ovarian cancer patients and to correlate levels with clinical factors in ovarian cancer patients. METHODS Archived samples from controls, patients with LMP tumors and ovarian cancer were tested using commercial assays, including serially collected serum and urine samples from women treated for stage III/IV serous ovarian cancer. RESULTS Five of 6 patients with stage I/II and 26 of 36 stage III/IV serous ovarian cancer patients had HE4-positive urines, similar to serum samples (4 of 5 stage I/II and 26 of 34 stage III/IV) when tested at the same level of specificity (95%). Urine HE4 was more sensitive in LMP tumors: 9 of 32 urines (28%) HE4-positive versus 3 of 68 sera (4.4%, p=0.002). Mean levels of serum CA125 and HE4 decreased comparably in patients during initial treatment regardless of their primary platinum response, but mean urine HE4 levels decreased only 7% in primary platinum resistant patients while decreasing 68% in those who were sensitive. By 7months after diagnosis, urine HE4 levels were higher in primary platinum resistant patients compared to those who proved to be sensitive (p=0.051) and persisted 12months after diagnosis (p=0.014). HE4 values in urine also became positive in advance of clinical recurrence in several women while serum HE4 and serum CA-125 remained normal. CONCLUSIONS Measuring HE4 in urine complements serum assays for the detection of ovarian cancer and may allow identification of patients at high risk for primary platinum resistance.

Therapeutic vaccines for ovarian cancer

While therapeutic vaccines for ovarian cancer represent only a small fraction of active clinical trials, growing interest in this area and the accumulated data supporting the use of vaccines in cancer treatment portend further expansion of trials incorporating these strategies. This review explores the rationale for the use of vaccines for the treatment of ovarian cancer. It examines vaccine platforms that have been investigated and reviews the data from these studies. We also highlight recently reported phase 2 and 3 clinical trials with clinical outcomes as endpoints. Finally, we consider directions for the next generation of vaccines in light of these findings and our emerging understanding of agents that may augment vaccine responses by targeting the immunosuppressive impact of the tumor microenvironment.

Route of hysterectomy and surgical outcomes from a statewide gynecologic oncology population: is there a role for vaginal hysterectomy?

BACKGROUND Recent policy changes by insurance companies have been instituted to encourage vaginal hysterectomy (VH) as the preferred route for removal of the uterus. It is not known if advantages of VH for benign indications apply to women with gynecologic cancer. OBJECTIVE The goal of this study was to assess trends in surgical approach to hysterectomy among gynecologic cancer patients and to evaluate outcomes by approach. We hypothesized that, among gynecologic oncology patients, postoperative complications and hospital stay would differ by surgical approach, and that advantages of VH for benign indications may not apply to gynecologic cancer patients. STUDY DESIGN We performed a population-based retrospective cohort study of cervical, endometrial, or ovarian/fallopian tube cancer patients treated surgically in Washington State from 2004 through 2013 using the Comprehensive Hospital Abstract Reporting System. Surgery was categorized as abdominal hysterectomy (AH), laparoscopic hysterectomy (LH), or VH. We determined rate of surgical approach by year and the association with length of stay, 30-day readmission rate, and perioperative complications. RESULTS We identified 10,117 patients who underwent surgery for gynecologic cancer, with 346 (3.4%) VH, 2698 (26.7%) LH, and 7073 (69.9%) AH. Patients undergoing AH had more comorbidities than patients with VH or LH (Charlson Comorbidity Index ≥2: 11.3%, 7.9%, and 8.1%, respectively; P < .001). From 2004 through 2013 AH and VH declined (94.4-47.9% and 4.4-0.8%, respectively; P < .001) while LH increased from 1.2-51.4% in 2013 (P < .001). Mean length of stay was 4.6 days for women undergoing AH and was 1.9 days shorter for VH (95% confidence interval, 1.6-2.3 days) and 2.6 days shorter for LH (95% confidence interval, 2.4-2.7 days) (P < .001). Risk of 30-day readmission for patients undergoing LH was 40% less likely compared to AH but not different for VH vs AH. CONCLUSION AH and LH remain the preferred routes for hysterectomy in gynecologic oncology. Over the past decade, there has been a significant shift to LH with lower 30-day readmission and complication rates. There may be a limited role for VH in select patients. Current efforts to standardize the surgical approach to hysterectomy should not apply to patients with known or suspected gynecologic cancer.

Recurrence patterns after extended treatment with bevacizumab for ovarian, fallopian tube, and primary peritoneal cancers.

OBJECTIVE To evaluate patterns of recurrence for ovarian, fallopian tube, and primary peritoneal cancer patients undergoing extended treatment with bevacizumab (BEV). METHODS A retrospective review of patients with primary ovarian, fallopian tube, or peritoneal cancer treated with BEV alone or in combination with other chemotherapy from 2001 to 2011 was performed. Qualified patients were identified by chemotherapy records. Electronic medical records, labs, and imaging reports were reviewed and abstracted. RESULTS Of 108 patients identified, 89 patients met study criteria by having disease progression either during treatment with BEV or after discontinuing BEV without initiating any other treatment. Patients on extended BEV therapy (>12 cycles) were more likely to recur in extra-visceral sites (p=0.04), especially in lymph nodes (p=0.0002), and presented with fewer symptoms at time of recurrence (p=0.02), compared to patients who had received ≤ 12 cycles. CA-125 becomes less reliable for the detection of recurrent disease with extended BEV therapy (p=0.03 for ≤12 cycles vs. p=0.08 for >12 cycles). Radiology was superior to CA-125, symptom, and physical exam, in detecting recurrence with extended BEV therapy (all p<0.0001). CONCLUSIONS Extended treatment with BEV in ovarian, fallopian tube, and peritoneal cancers results in alterations in the patterns of recurrence. Radiologic imaging is more reliable than CA-125, symptoms, or physical exam, in identifying recurrent disease in patients undergoing BEV treatment. As novel targeted therapies continue to be employed, guidelines for gynecologic cancer surveillance must continue to be reexamined.