Dennis Yi-Shin Kuo

Taxol-resistant epithelial ovarian tumors are associated with altered expression of specific beta-tubulin isotypes.

The treatment of advanced ovarian cancer with taxol is hindered by the development of drug resistance. The cellular target for taxol is the microtubule that is stabilized by the drug. Taxol preferentially binds to the beta subunit of tubulin of which there are six distinct isotypes in mammalian cells. We have used highly specific oligonucleotides and polymerase chain reaction to analyze expression of all six beta-tubulin genes. Human lung cancer cells (A549) were selected in 12 and 24 nM taxol resulting in cell lines that were 9- and 17-fold resistant, respectively. These cells displayed an altered ratio of classes I, II, III, and IVa beta-tubulin isotypes. Ovarian tumors, seven untreated primary and four taxol- resistant tumor-bearing ascites, displayed significant increases (P < 0.005) in classes I (3.6-fold), III (4.4-fold), and IVa (7.6-fold) isotypes in the taxol-resistant samples as compared with untreated primary ovarian tumors. The increased expression appears to be related to the resistance phenotype, as the basal levels of the class III and IVa isotypes in the untreated tumors were extremely low. This is the first report of altered expression of specific beta-tubulin genes in taxol-resistant ovarian tumors and we propose that the latter may play a role in clinical resistance to taxol.

Abstract 5020: Potential lifestyle intervention in inner city women with endometrial cancer: A pilot study

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Hypothesis: Evidence suggests that modification of diet and exercise practices may prevent cancer recurrence. It may also decrease the risk factors for the leading causes of death in women including heart disease and stroke. Methods: 100 patients with previously diagnosed endometrial cancer were enrolled in a pilot study to collect data regarding current lifestyle, willingness to change and preferred programs of nutrition and exercise. All enrolled subjects were verbally asked to respond to a questionnaire that included validated and novel instruments. Results: Mean age was 64 (39-86 years) and mean body mass index was 34 kg/m2 (17-55). 38% of the responders were Black/African American, 33% were Caucasian, and 21% were Hispanic. Of these, 69% were born in the United States of America. 75% described themselves as “overweight”. The most common mode of current exercise was walking (54%). 89% of the patients responded that they would be interested in participating in a diet or exercise program. The most common reason that women stated they would want to participate was to improve overall health (48%). Only 4% stated that they thought it would prevent recurrence of their cancers. Diabetes mellitus was previously diagnosed in 30% of participants. Eighty three percent of diabetic patients had body mass index over 30 kg/m2 and 30% had body mass index over 40 kg/m2. Eleven patients currently on therapy for diabetes had hemoglobin A1C values greater then 6.5 and are at risk for microvessel damage and end-organ dysfunction including kidney failure and impaired vision Discussion: These data present the opinions of a racially heterogeneous group of women at risk for cancer recurrence, as well as the morbidity and mortality related to obesity and diabetes. These data suggest that women at our center should participate in a dietary and exercise intervention program and our patients would benefit from the additional health education. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5020. doi:10.1158/1538-7445.AM2011-5020

Pregnancy-associated subacute hemorrhage into a prolactinoma resulting in diabetes insipidus

A young woman with a small pituitary tumor associated with hyperprolactinemia developed subacute intrapituitary hemorrhage during the third trimester of pregnancy and presented with central diabetes insipidus. Magnetic resonance imaging established the diagnosis. After transsphenoidal surgery, her visual findings resolved, and the patient had an uneventful spontaneous delivery.

A phase II study of weekly topotecan and docetaxel in heavily treated patients with recurrent uterine and ovarian cancers

OBJECTIVES A phase II trial designed to evaluate the safety and efficacy of weekly topotecan and docetaxel in heavily treated patients with recurrent uterine or epithelial ovarian cancers. METHODS Eligible patients with recurrent epithelial ovarian or uterine cancers were treated with weekly topotecan 3.5 mg/m(2) and docetaxel 30 mg/m(2) for 3 consecutive weeks. Cycles were repeated every 4 weeks for 6 cycles or until evidence of disease progression, unacceptable toxicity, or death. Response was assessed as per RECIST or Rustins criteria. Time to best response and overall survival were calculated using Kaplan-Meier statistical methods. RESULTS Twenty-seven patients registered, of which 24 were evaluable for response. The majority of patients had received 2 prior chemotherapy regimens. Of the total 86 cycles of chemotherapy that were administered, there were three grade 4 (all neutropenia) and ten grade 3 toxicities. Six of the grade 3 non-hematologic toxicities were unrelated to treatment. There were 8 dose delays and 4 dose reductions. The overall response rate was 25% (95% CI: 7.7%-42.3%, 8% CR, 17% PR), and 38% of the patients had clinical benefit (95% CI: 18.1%-56.9%; CR+PR+13% SD). The median duration of response was 8.5 months (range 3-19 months). The median overall survival was 18.5 months (range 1.8-50.7 months). CONCLUSION The combination of weekly topotecan and docetaxel has clinical benefit and is well tolerated in this heavily treated patient population. Patients with platinum-resistant tumors had clinical benefit and should be considered for further study with this regimen.

Novel neurosensory testing in cancer patients treated with the epothilone B analog, ixabepilone

BACKGROUND We have previously established the recommended phase II dose (RPTD) of ixabepilone as 40 mg/m(2) administered over 1 h repeated every 3 weeks with neuropathy as a cumulative dose-limiting toxicity. We expanded the cohort at the RPTD to include detailed assessment of nerve damage in these patients. We report our findings on vibration perception threshold (VPT) and neuropathy. PATIENTS AND METHODS Forty-four patients were treated with a median (range) of three (1-14) cycles of ixabepilone. The VPT (5-min duration) and nerve conduction test (NCT, 10-min duration) were carried out in the office, before ixabepilone dosing, and every two cycles thereafter. RESULTS Neuropathy (grade 1 and grades 2-3) was observed in 17 (38.6%) and 11 (25%) patients, respectively. The mean increase in VPT as a function of grade 0-1 versus grades 2-3 neuropathy was 0.235 +/- 0.03 versus 0.869 +/- 0.09 (P = 0.049) vibration units. The F-wave frequency and distal motor latency, as assessed using the NCT, did not correlate with clinical neurotoxicity. CONCLUSION The change in VPT is observed early and likely reflects early vibration perception change. Mean change in VPT correlates with the severity of clinical neuropathy. Whether VPT change predicts onset of severe neuropathy warrants prospective testing and validation.

Side‐docking in robotic‐assisted gynaecologic cancer surgery

The majority of previous experience with the robotic‐sssisted laparoscopic technique for gynaecological procedures has utilized a method in which the robot is centrally located (CD) between the patients legs.

Paclitaxel plus oxaliplatin for recurrent or metastatic cervical cancer: a New York Cancer Consortium Study.

OBJECTIVE Survival in women with recurrent or metastatic cervical cancer remains poor. More effective and less toxic regimens are needed. Cisplatin is an effective radiosensitizer, but its single agent activity in recurrent cervical cancer, especially after prior cisplatin exposure, is disappointing, with a response rate of only 13%. Oxaliplatin has preclinical activity in cisplatin-resistant tumors and may have synergic activity when combined with paclitaxel. Our objective is to determine the efficacy and toxicity of paclitaxel and oxaliplatin in patients with recurrent or metastatic cervical cancer. METHODS Patients with histologic confirmation of primary metastatic or recurrent cervical cancer not amenable to surgical management were eligible. Treatment consisted of paclitaxel 175 mg/m(2) IV and oxaliplatin 130 mg/m(2) IV every 21 days. The primary endpoints were toxicity, recorded every cycle, and response, determined by RECIST criteria and were assessed every 9 weeks, with subsequent confirmation as required. Sample size determinations were made using a Simons two-stage design with a projected overall response proportion of 13% with cisplatin alone. Survival rates were calculated with Kaplan-Meier methods. RESULTS Of the 35 patients enrolled, 32 were evaluable. The median age was 56 (27-78); 30 had had prior radiation (23 concomitant with cisplatin). Patients completed a mean of 4.2 cycles (1-11). There were 2 complete and 5 partial responses for a total response rate of 7/32 (22%; 95% CI: 9.3%-40.0%). Eight patients had stable disease for an overall clinical benefit rate of 15/32 (47%; 95% CI: 29.1%-65.3%). The mean time to best response was 13.5 weeks (95% CI: 10.6, 16.4). The mean progression-free survival was 21 weeks (95% CI: 14.7, 27.2) and mean overall survival was 52 weeks (95% CI: 39.4, 64.8). A total of 135 cycles were administered. There were 28 (20.1%) grade 3/4 hematologic toxicities and 46 (34.1%) grade 3/4 non-hematologic toxicities, which were predominantly sensory neuropathy. There were 13 treatment delays, 4 dose reductions, and no treatment-related deaths. CONCLUSIONS The combination of paclitaxel and oxaliplatin is an effective regimen in patients with recurrent or persistent cervical cancer including a majority previously exposed to cisplatin. Further study and comparison with other platinum-based regimens is warranted.

Gynaecologic effects of tamoxifen.

Tamoxifen, an estrogen antagonist, is widely used as adjuvant therapy in patients with breast cancer. Its efficacy in increasing survival and reducing recurrence rates has been demonstrated in several European and American studies. However, its effects appear to be tissue specific. Tamoxifen exerts an estrogen effect (agonist) on the endometrium, myometrium and vagina. An increase in uterine cancer has been confirmed in several placebo-controlled clinical trials. Due to the widespread use of this drug, it is timely to review the gynecologic effects of tamoxifen.

Physical activity for an ethnically diverse sample of endometrial cancer survivors: A needs assessment and pilot intervention

Objective To determine the physical activity (PA) behavior, needs and preferences for underserved, ethnically diverse women with a history of endometrial cancer (EC). Methods Women with a history of EC (41 non-Hispanic black, 40 non-Hispanic white, and 18 Hispanic) completed a needs assessment during their regular follow-up appointments at Montefiore Medical Center in Bronx, NY, USA. An 8-week pilot PA intervention based on the results of the needs assessment was conducted with 5 EC survivors. Results Mean body mass index (BMI) among the 99 respondents was 34.1±7.6 kg/m2, and 66% did not exercise regularly. Self-described weight status was significantly lower than actual BMI category (p<0.001). Of the 86% who were interested in joining an exercise program, 95% were willing to attend at least once weekly. The primary motivations were improving health, losing weight, and feeling better physically. Despite the high interest in participation, volunteer rate was very low (8%). However, adherence to the 8-week pilot PA intervention was high (83%), and there were no adverse events. Body weight decreased in all pilot participants. Conclusion These data show that ethnically diverse EC survivors have a great need for, and are highly interested in, PA interventions. However, greater care needs to be taken to assess and identify barriers to increase participation in such programs.

Delayed Presentation of Vaginal Cuff Dehiscence after Robotic Hysterectomy for Gynecologic Cancer: A Case Series and Review of the Literature.

Background. Vaginal cuff dehiscence after hysterectomy has varying incidence according to surgical approach, with highest rates associated with laparoscopic surgery. Comparative data on timing of diagnosis describe a wide range of clinical presentation from weeks to years after hysterectomy. Limited reports have focused specifically on delayed presentation of vaginal cuff dehiscence. Cases. All cases of vaginal cuff dehiscence at our institution between 2005 and 2015 were collectively reviewed and three cases were identified of women who presented with cuff dehiscence greater than 180 days from index surgery. Diagnosis occurred at 342 to 461 days after operation. One patient presented with abdominal pain, a second case presented with vaginal discharge, and the third case lacked clinical symptoms altogether. Prior to diagnosis, one case received chemotherapy and external beam radiation for Stage IB1 cervical cancer and another case received external beam radiation alone for Stage II endometrioid adenocarcinoma. All cuffs were repaired vaginally with interrupted, early absorbable suture. Conclusion. Robotic total laparoscopic hysterectomy may be associated with increased risk of vaginal cuff dehiscence. Further studies are needed to determine risk factors and patient characteristics associated with delayed presentation of vaginal cuff dehiscence in robotic total hysterectomy as well as all surgical approaches.