Peter Dottino

Secondary cytoreduction for ovarian cancer following cisplatin therapy.

PURPOSE This study was undertaken to evaluate the efficacy of secondary surgical cytoreduction in the management of ovarian cancer. PATIENTS AND METHODS The cases of 100 patients with recurrent or progressive epithelial ovarian cancer whose initial treatment had been cytoreduction followed by cytotoxic therapy with a cisplatin-based regimen were reviewed. All 100 patients underwent surgery, after recurrence or progression was documented preoperatively, by gynecologic oncologists at the Mount Sinai Medical Center, New York, NY, between 1980 and 1991 with the intention of performing radical tumor reduction. RESULTS Sixty-one patients had a secondary cytoreduction that left residual disease less than 2 cm in diameter. The median survival, determined from the date of the secondary cytoreduction to the date of death or last follow-up, is 27.1 months in the optimally treated group and 9.0 months for the 39 patients whose surgery was suboptimal (P = .0001). Other variables associated with statistically significant longer survival, and a significantly higher probability of achieving a successful secondary cytoreduction, included age < or = 55 years at the time of secondary cytoreduction, interval from initial diagnosis to secondary cytoreduction of more than 12 months, residual disease at initial staging laparotomy of less than 2 cm, and a complete clinical response to a cisplatin-based front-line regimen. Multivariate analysis confirms the survival benefit provided by a successful secondary cytoreduction when adjusted for the above variables. There was one postoperative mortality. Ten percent of the successfully cytoreduced patients and 18% of the unsuccessfully cytoreduced patients experienced some degree of postoperative morbidity. CONCLUSION These data justify the performance of secondary cytoreductive surgery for patients who develop gross recurrent or progressive ovarian cancer following cisplatin therapy.

Ovarian intraepithelial neoplasia demonstrated in patients with stage I ovarian carcinoma

Retrospective review of sections of ovary from 50 patients with stage I, grade 1-3, epithelial ovarian carcinoma was performed to assess presence of cellular and nuclear atypia in noncancerous tissue adjacent to the primary tumor; ovarian tissue from 50 patients undergoing incidental oophorectomy was reviewed as well. Atypia was more common in cancer patients, and finding the combination of nuclear atypia, defined as presence of pleomorphism or irregular chromatin distribution, with cellular atypia, defined as presence of stratification or loss of polarity, allowed separation of cancer and control groups with 98% sensitivity and 100% specificity. Presence of nuclear and cellular atypia was used to define ovarian intraepithelial neoplasia (OIN). If OIN is demonstrated to precede ovarian carcinoma, then it may offer insights into the development of ovarian cancer and may eventually increase the feasibility of screening for this disease.

A new technique for performing syed-neblett template interstitial implants for gynecologic malignancies using transrectal-ultrasound guidance

PURPOSE Interstitial brachytherapy plays an important role in the treatment of advanced and recurrent gynecologic malignancies. Unfortunately, the inability to visualize the tumor and surrounding normal structures during the implant has hampered the accuracy and safety of the implant. Transrectal ultrasound guided Syed-Neblett template implantation is a new technique for performing interstitial implants under direct visualization. The details of the technique are presented to demonstrate the ability to accurately guide needle placement into tumor and avoid needle insertion into critical surrounding normal structures. METHODS AND MATERIALS The transrectal ultrasound is positioned so that it can visualize the tumor, and normal surrounding structures in both transverse and longitudinal planes. The Syed-Neblett template is positioned and sutured into the perineum. Needles are inserted into the target area under direct visualization through transverse imaging. The bladder and rectum can be directly imaged and thus avoided. Longitudinal imaging is then used to guide the needles to the appropriate depth. In addition, it can be used to assess the length of the target volume and aid in determining the active length of the sources. RESULTS A total of 12 procedures have been performed on seven patients from August 30, 1995 to April 12, 1996. The presenting diseases included: Stage IIIb cervical cancer in four cases, recurrent endometrial cancer in two cases, and Stage III vaginal cancer in one case. The total length of time for implantation of the needles ranged from 45 to 165 min (median--130 min). CONCLUSION Transrectal ultrasound guidance provides real-time visualization of the target volume and normal tissues during interstitial implantation of gynecologic malignancies and allows for accurate needle placement.

Laparoscopic management of adnexal masses in premenopausal and postmenopausal women

OBJECTIVE To evaluate the feasibility and safety of laparoscopic adnexal mass removal in patients without preselection for benign pathology and assess the operative complications and findings. METHODS All patients presenting to the gynecologic oncology service between April 1992 and April 1996 with adnexal masses were candidates for laparoscopic management. Patients underwent preoperative radiological studies and office pelvic examination. Laparoscopic management was attempted on patients without evidence of gross metastatic disease or masses that extended above the umbilicus. Laparotomy was performed if indicated by pathologic findings or technical difficulty. All removed adnexal masses were sent for immediate pathologic diagnosis. The type of procedure, intraoperative findings, and complications were all recorded at the time of procedure. RESULTS One hundred sixty patients underwent laparoscopic evaluation for an adnexal mass. Benign pathology was discovered in 139 (87%, 95% confidence interval [CI] 84, 90) patients, and 141 (88%, 95% CI 86, 91) patients were managed laparoscopically. Reasons for laparotomy included technical difficulty, operative complications, or malignancy. Frozen section diagnosis was concordant with the final pathology reports in all but five patients (97% concordance), and no discrepancies resulted in treatment delays. CONCLUSION Laparoscopic management of adnexal masses can be successful in a gynecologic oncology population if there is expertise in operative laparoscopy, availability of immediate accurate pathologic examination, and appropriate further treatment where indicated.

Staging of cervical carcinoma: accuracy of magnetic resonance imaging and computed tomography.

A prospective study was undertaken to assess the ability of magnetic resonance imaging (MRI) to stage cervical carcinoma. Compared to computed tomography (CT), MRI showed a high degree of accuracy in correctly demonstrating involvement of the vagina, parametria and sidewalls, bladder, and lymph nodes but tended to overestimate disease in all of the categories studied. Large-scale studies comparing the two modalities are necessary because the most accurate staging of cervical carcinoma is crucial for selecting the best treatment protocols.

Personalized Circulating Tumor DNA Biomarkers Dynamically Predict Treatment Response and Survival In Gynecologic Cancers

Background High-grade serous ovarian and endometrial cancers are the most lethal female reproductive tract malignancies worldwide. In part, failure to treat these two aggressive cancers successfully centers on the fact that while the majority of patients are diagnosed based on current surveillance strategies as having a complete clinical response to their primary therapy, nearly half will develop disease recurrence within 18 months and the majority will die from disease recurrence within 5 years. Moreover, no currently used biomarkers or imaging studies can predict outcome following initial treatment. Circulating tumor DNA (ctDNA) represents a theoretically powerful biomarker for detecting otherwise occult disease. We therefore explored the use of personalized ctDNA markers as both a surveillance and prognostic biomarker in gynecologic cancers and compared this to current FDA-approved surveillance tools. Methods and Findings Tumor and serum samples were collected at time of surgery and then throughout treatment course for 44 patients with gynecologic cancers, representing 22 ovarian cancer cases, 17 uterine cancer cases, one peritoneal, three fallopian tube, and one patient with synchronous fallopian tube and uterine cancer. Patient/tumor-specific mutations were identified using whole-exome and targeted gene sequencing and ctDNA levels quantified using droplet digital PCR. CtDNA was detected in 93.8% of patients for whom probes were designed and levels were highly correlated with CA-125 serum and computed tomography (CT) scanning results. In six patients, ctDNA detected the presence of cancer even when CT scanning was negative and, on average, had a predictive lead time of seven months over CT imaging. Most notably, undetectable levels of ctDNA at six months following initial treatment was associated with markedly improved progression free and overall survival. Conclusions Detection of residual disease in gynecologic, and indeed all cancers, represents a diagnostic dilemma and a potential critical inflection point in precision medicine. This study suggests that the use of personalized ctDNA biomarkers in gynecologic cancers can identify the presence of residual tumor while also more dynamically predicting response to treatment relative to currently used serum and imaging studies. Of particular interest, ctDNA was an independent predictor of survival in patients with ovarian and endometrial cancers. Earlier recognition of disease persistence and/or recurrence and the ability to stratify into better and worse outcome groups through ctDNA surveillance may open the window for improved survival and quality and life in these cancers.

Combined chemotherapy and radiation therapy for advanced carcinoma of the cervix

Ten patients with advanced squamous cell carcinoma of the uterine cervix received induction chemotherapy with cis-platinum, mitomycin-C, vincristine, and bleomycin (BOMP) over a 5 week period, followed by radiotherapy with concomitant weekly cisplatinum. Two patients were FIGO stage I-B barrel-shaped, five were stage II-B, and three were III-B. All patients responded to induction chemotherapy with five complete and five partial responses. At the completion of radiation therapy, nine patients had negative biopsies. One patient never reached a complete response and died of distant metastasis. Another underwent total exenteration for a central recurrence and was found to have microscopic paraaortic lymph node involvement. A third recurred in the parametrium. Two patients with barrel-shaped tumors underwent extrafascial hysterectomies; both had negative specimens and tolerated surgery well. Although follow-up is short, this new approach for advanced carcinoma of the cervix yielded excellent results and was well tolerated.

A critical re-appraisal of BRCA1 methylation studies in ovarian cancer

A central challenge facing gynecologic oncology is achieving personalized care in ovarian cancer treatment. The current ovarian cancer classification scheme distinguishes tumors based on histopathologic subtype, grade, and surgical stage. Recent molecular investigations have highlighted distinguishing genetic features of certain tumors within a given category, and given the rapid pace of technologic advancement combined with plummeting costs for complete genomic sequencing this classification will markedly improve. Clinical studies have begun to explore the influence of currently known distinctions on the natural history of the disease, most recently with particular attention to the BRCA1 status of tumors. Mutations in the BRCA1 gene have long been known to increase a womans risk of developing ovarian cancer. As has been shown, BRCA1-associated ovarian cancers may be associated with characteristic differences in therapeutic response and overall survival, and further defining these subsets may become instrumental in clinical decision-making. Therefore, given the eightfold difference (5-40%) in reported frequency of BRCA1 inactivation by methylation in the pioneering studies in the field, a critical re-appraisal of the literature, techniques, samples used, and interpretations of BRCA1 inactivation is warranted along with a review of the more recent and comprehensive molecular studies.

Decreased levels of serum glutathione peroxidase 3 are associated with papillary serous ovarian cancer and disease progression

BackgroundGlutathione peroxidase 3 (GPX3) is a selenocysteine-containing antioxidant enzyme that reacts with hydrogen peroxide and soluble fatty acid hydroperoxides, thereby helping to maintain redox balance within cells. Serum levels of GPX3 have been found to be reduced in various cancers including prostrate, thyroid, colorectal, breast and gastric cancers. Intriguingly, GPX3 has been reported to be upregulated in clear cell ovarian cancer tissues and thus may have implications in chemotherapeutic resistance. Since clear cell and serous subtypes of ovarian cancer represent two distinct disease entities, the aim of this study was to determine GPX3 levels in serous ovarian cancer patients and establish its potential as a biomarker for detection and/or surveillance of papillary serous ovarian cancer, the most frequent form of ovarian tumors in women.Patients and MethodsSerum was obtained from 66 patients (median age: 62 years, range: 22-89) prior to surgery and 65 controls with a comparable age-range (median age: 53 years, range: 25-83). ELISA was used to determine the levels of serum GPX3. The Mann Whitney U test was performed to determine statistical significance between the levels of serum GPX3 in patients and controls.ResultsSerum levels of GPX3 were found to be significantly lower in patients than controls (p = 1 × 10-2). Furthermore, this was found to be dependent on the stage of disease. While levels in early stage (I/II) patients showed no significant difference when compared to controls, there was a significant reduction in late stage (III/IV, p = 9 × 10-4) and recurrent (p = 1 × 10-2) patients. There was a statistically significant reduction in levels of GPX3 between early and late stage (p = 5 × 10-4) as well as early and recurrent (p = 1 × 10-2) patients. Comparison of women and controls stratified to include only women at or above 50 years of age shows that the same trends were maintained and the differences became more statistically significant.ConclusionsSerum GPX3 levels are decreased in women with papillary serous ovarian cancer in a stage-dependent manner and also decreased in women with disease recurrence. Whether this decrease represents a general feature in response to the disease or a link to the progression of the cancer is unknown. Understanding this relationship may have clinical and therapeutic consequences for women with papillary serous adenocarcinoma.

Alterations in Nuclear Pore Architecture Allow Cancer Cell Entry into or Exit from Drug-Resistant Dormancy

Phenotypic diversity arises in tumors just as it does in developing organisms, and tumor recurrence frequently manifests from the selective survival of divergent drug-resistant cells. Although the expanding tumor cell population may be successfully targeted, drug-resistant cells may persist and sustain the tumor or enter dormancy before igniting a future relapse. Herein, we show that partial knockdown of nucleoporin p62 (NUP62) by small-interfering RNA confers cisplatin resistance to cultured high-grade ovarian carcinoma cells. Treatment with NUP62 small-interfering RNA and cisplatin leaves resistant cells in a state of dormancy; some dormant cells can be induced to proliferate by transient induction of NUP62 expression from an ectopic expression construct. In addition to suggesting functional links between nuclear pore complex architecture and cancer cell survival, the culture system provides a novel experimental window into the dynamics of tumor cell drug resistance and dormancy.