Choices in creating continent urostomies following pelvic exenteration for gynecologic malignancies.

OBJECTIVE: The purpose of this report was to describe a rationale for choosing from a variety of techniques to construct continent urinary diversions for patients who undergo pelvic exenterations. Moreover, this report evaluated the technique and utility of a continent urostomy created from a supracecal segment of colon. METHODS: The charts from patients who underwent pelvic exenterations and urinary diversions by DFS between September 1999 and December 2000 were reviewed after institutional review board approval. Data were recorded and evaluated. RESULTS: Four patients underwent total pelvic exenterations and one received an anterior exenteration. Recurrent vulvar, vaginal, and cervical cancers were diagnosed in one, one, and two of the patients. One patient had an unknown primary squamous cell carcinoma in the pelvis. Four of the five received prior pelvic radiotherapy either in the neoadjuvant setting or as treatment for their primary disease. All five patients chose to have continent urostomies constructed. One Kock (ileal) pouch, one Miami (iliocolonic) pouch, and three supracecal colonic continent urostomies (SCCCU) were built. All five maintained continence over the follow-up period (mean follow-up time = 8.2 months). No complications related to the urostomies required reoperation. A new technique to for the construction of a SCCCU is described. CONCLUSION: With a variety of procedures established to build continent urostomies, the choice of which to use should be individualized to the patient's situation as well as to the surgeon's experience. The use of a SCCCU requires moderately complex manipulations of the colon (described in the text) and a slight increase in the operative time; however, it results in successful continence and avoids complications related to radiation-injured bowel. It may be considered the procedure of choice for patients who have received prior radiation therapy. Long-term follow-up is needed.

A vaginal and extraperitoneal approach to surgically stage patients with endometrial cancer.

OBJECTIVE: The purpose of this project was to prospectively evaluate the feasibility of an alternative technique for surgically staging patients with endometrial cancer. METHODS: Patients with endometrial cancer were enrolled in this protocol from September 1999 until August 2000. The staging procedure included pelvic washings via colpotomy, total vaginal hysterectomy, bilateral salpingo-oophorectomy (TVH/BSO), and extraperitoneal pelvic and paraaortic lymphadenectomy (EP-LND) if indicated. Tumor characteristics, time and feasibility of surgical procedures, length of hospital stays, and complications were prospectively recorded. RESULTS: Twenty-one patients were enrolled. Grade 1, 2, and 3 tumors were identified in 6 (29%), 10 (48%), and 5 (24%) patients, respectively. Pelvic washings and TVH/BSOs were performed on all patients. A total of 21/21 (100%) uterine specimens were removed vaginally and 41/42 (98%) adnexa were resected vaginally. EP-LNDs were performed on 17 (81%) patients due to pathologic findings of the uterine specimens. The median time to perform a TVH/BSO was 68 (47-149) min. The median time to complete a EP-LND was 77 (59-107) min. The median number of postoperative days was 1 (1-5). Complications were infrequent and mild. CONCLUSIONS: TVH/BSO, pelvic washings, and EP-LND is a feasible alternative to standard surgical staging of endometrial cancer. The minimal amount of exposure to the intraperitoneal space makes this approach arguably the least invasive for endometrial cancer staging and accounts for the decrease in recovery time and shortened hospital stays. The acceptable length of surgical time, short hospital stays, and minimal requirements for surgical instruments make this approach potentially the most cost-effective option for surgically staging patients with endometrial cancer. A randomized trial comparing this technique to standard surgical staging is warranted.

Flt-3 ligand inhibits growth of human ovarian tumors engrafted in severe combined immunodeficient mice.

OBJECTIVE: The current study evaluated the effects of Flt-3 ligand (FL) on the growth of human malignant ovarian tumors engrafted in severe combined immunodeficient (SCID) mice with particular attention directed at FL's effect on the host natural killer (NK) cell response against ovarian cancer xenografts. METHODS: Equal portions of surgical specimen-derived human ovarian carcinomas were engrafted subcutaneously (SC) into SCID mice. Mice were placed into one of two treatment groups 7 days after the day of implantation. Group 1 received placebo injections SC from Day 1 to Day 20 and group 2 received FL at 10 microg/day SC from Day 1 to Day 20. NK cell depletion was performed on three additional mice from group 2 starting on Day 0 using anti-asialo GM1. Serial tumor volumes were measured. On Day 21, mice from each group were sacrificed, and tumors and spleens were evaluated. Data analysis included chi(2) tests, Student t tests, and analyses of variance when appropriate. RESULTS: FL resulted in tumor growth delay compared with control (P = 0.036). When NK cell activity was depleted prior to FL administration, no tumor growth delay was observed. Spleens from FL-treated mice were larger (P < 0.01) with expanded white pulp compared with controls. Histologic examination of tumor sections from FL-treated mice revealed regions of solid tumor growth with glandular architecture similar to that seen in control tumors; however, there was an obvious increase in regions composed largely of dense fibrosis in the FL-treated tumors. NK cells and other infiltrating cells could be detected in clusters among tumors from mice treated with FL whereas these cells were only occasionally detected in sections of control tumors. CONCLUSION: FL treatment resulted in an antitumor response against human ovarian cancer engrafted in SCID mice and this inhibition appears to be largely host NK cell mediated. The tumor inhibition seen in this model is similar to that previously seen using syngeneic tumors grown in an immunocompetent animal model. Results from this model can potentially be extrapolated to treatment of human ovarian cancer patients.

Gemcitabine salvage chemotherapy for patients with gynecologic malignancies of the ovary, fallopian tube, and peritoneum.

The efficacy and toxicity of gemcitabine salvage chemotherapy was evaluated in 27 heavily pretreated patients with recurrent and progressive ovarian, fallopian tube, or peritoneal cancer. At least one platinum-based chemotherapeutic regimen had failed in each patient. The median number of previous chemotherapy regimens and cycles of chemotherapy was 4 and 23, respectively. A total of 124 cycles of gemcitabine were delivered (median, 3 cycles). Hematologic toxicity included four patients with grade 3/4 thrombocytopenia and two patients with grade 3/4 neutropenia. Thrombocytopenia and neutropenia resulted in eight dose reductions and a single 1-week treatment delay. Nonhematologic side effects were well tolerated and largely self-limiting. No complete responses were observed. Three patients (11%) demonstrated partial responses to therapy. The duration of response was 7 months for two of the responders and 5 months for the third responder. Stable disease was observed in 14 patients (52%), in whom the median progression-free interval was 5 months. In conclusion, among heavily pretreated patients, gemcitabine has limited antitumor activity in platinum-resistant carcinomas of the ovary, fallopian tube, and peritoneum. The role of gemcitabine in the treatment of gynecologic malignancies of the ovary, fallopian tube, and peritoneum will be determined by studies that define the efficacy of multiagent regimens of chemotherapy that include gemcitabine and by studies that include patients who have been less heavily pretreated.

Recombinant growth hormone's effects on the strength and thickness of radiation-injured ileal anastomoses: a rat model.

BACKGROUND: Small bowel resections following radiotherapy for gynecologic cancers have resulted in significant rates of morbidity and mortality. The objective of this study was to evaluate the effect of rGH on the breaking strength and thickness of radiation-injured ileal anastomoses in an animal model. MATERIALS AND METHODS: Sprague-Dawley rats were treated with 1800 cGy of pelvic irradiation in a single fractionation. Seventeen weeks following pelvic teletherapy an ileo-ileostomy was performed. The rats were randomized to receive 2.0 mg/kg/day of rGH for 7 days or placebo. On the seventh postoperative day a segment of ileum surrounding the anastomosis was resected. The segments were tested for breaking strength or were histologically measured for anastomotic thickness. RESULTS: The ileal anastomotic breaking strength in the rGH group was 181 +/- 8.4 g (mean +/- standard error). The breaking strength of ileal anastomoses in the placebo group was 133 +/- 6.9 g (P < 0.05). The rGH group demonstrated a greater anastomotic thickness (1.65 +/- 0.116 mm) than the placebo group (1.17 +/- 0.113 mm, P < 0.05). Of placebo rats 14.7% developed anastomotic leaks compared to 0% of rGH-treated animals (P < 0.05). CONCLUSIONS: RGH increased the ileal anastomotic breaking strength by 36% in radiated rats. The anastomotic leak rate was reduced from 14.7% in the placebo group to 0% in the rGH group. These findings correlated with a 41% increase in the thickness of the anastomotic connective tissue in the rGH group. Clinical investigation in selected patients is warranted.

Effects of recombinant human erythropoietin on the antitumor effect of cisplatin in SCID mice bearing human ovarian cancer: A possible oxygen effect.

PURPOSE: Experiments were designed to evaluate the effect of an elevated hematocrit using recombinant human erythropoietin (Epo) on the antitumor response of cisplatin on human ovarian cancer engrafted in mice. METHODS: Forty female severe combined immunodeficient (SCID) mice with large human ovarian cancer xenografts implanted on the gonadal fat pad (GFP) and 40 female SCID mice with small subcutaneous (sq) human ovarian cancer xenografts were placed in one of four treatment groups. Group 1 (controls) received phosphate-buffered saline injections. Group 2 (Epo group) received Epo at 20 units three times per week. Group 3 (cisplatin group) received cisplatin at 5 mg/kg/week. Group 4 (Epo + cisplatin group) received Epo and cisplatin as above. Cisplatin was administered on day 0 for mice bearing large GFP tumors and was injected on days 0 and +7 for mice bearing small sq tumors. Epo injections were started on day -15 and continued until the completion of the experiment. Evaluations of the tumor growth, hematocrits, and performance status were made. The experiments were repeated in 24 SCID mice bearing small sq tumor xenografts with similar results. Representative data were reported. RESULTS: Among mice bearing large GFP tumors, a tumor growth delay was noted in the groups that received cisplatin with or without Epo compared to controls (P < 0.05). However, significant tumor growth delay could not be reached for mice in the Epo + cisplatin group compared to the cisplatin group (P = 0.07). Among mice bearing small sq tumors, a significant improvement in tumor regression was achieved in the Epo + cisplatin group compared to the cisplatin group (P < 0.05). No difference in tumor growth resulted in the Epo group compared to controls. Epo resulted in a 25-35% increase in the hematocrit in both the Epo group and the Epo + cisplatin group (P < 0.01). Mice in the control and in the Epo groups remained healthy. Mice treated with cisplatin developed objective signs of morbidity; however, performance scores for mice in the Epo + cisplatin group remained lower than scores in the cisplatin group. CONCLUSIONS: The data demonstrate a cisplatin-sensitizing effect on human ovarian cancer in SCID mice induced by the pretreatment elevation and maintenance of the hematocrit using Epo. These findings are consistent with an oxygen sensitization of cisplatin. Corroboration of these results may have significant clinical implications for the treatment of solid tumor patients.

Effects of IL-12 on human ovarian tumors engrafted into SCID mice.

OBJECTIVE: The effects of murine interleuken (IL)-12 on the growth of surgical specimen-derived malignant human ovarian tumors engrafted in severe combined immunodeficient (SCID) mice were assessed. The SCID mouse model facilitated the evaluation IL-12's effect on the host innate immune response against human ovarian cancer xenografts. METHODS: Equal portions of specimen-derived human ovarian carcinoma were engrafted subcutaneously into SCID mice. After 7 days, mice were placed into one of two treatment groups: (1) placebo/control or (2) murine IL-12 (0.33 mcg/day intraperitoneally x 20 days). Anti-asialo GM1 was administered on day 0 to 3 mice from the IL-12-treated group. Serial tumor volumes were measured. On day 21, mice from each group were sacrificed, and tumors and spleens were evaluated. Data analysis included chi2 tests, Student t tests, and analysis of variance when appropriate. The entire experiment was repeated for a total of three times with similar results. A total of 45 mice and two different human tumor specimens were utilized. Representative data were reported. RESULTS: IL-12 resulted in mean tumor growth delay and regression when compared to controls (P = 0. 02). Among the IL-12 group, 22% (2/9) developed complete remissions. When anti-asialo GM1 was added prior to IL-12, no tumor growth delay was noted. Splenic weights were higher among IL-12-treated mice compared to controls (P < 0.01). Spleen sections demonstrated expanded white pulp among IL-12-treated mice compared to controls. Histologic evaluation of tumor sections revealed central necrosis among tumors from mice treated with IL-12. Immunohistochemical stains identified increased numbers of NK cells in clusters within tumors from mice treated with IL-12 whereas NK cells were found to be sparsely scattered in control tumors. CONCLUSIONS: Murine IL-12 treatment resulted in significant tumor growth delay and tumor regression in SCID mice engrafted with human ovarian cancer. The data support an immunologic basis for the observed anti-tumor effects and suggest a role for NK cells as part of the effector pool. The current data support the clinical evaluation of IL-12 in the treatment of epithelial ovarian cancer.

Characterization of human ovarian carcinomas in a SCID mouse model.

This study characterizes a murine model which is promising for the study of the growth and natural history of ovarian cancer and for testing of new therapies for its treatment. Intact portions of 20 different human ovarian cancer surgical specimens were implanted in over 60 severe combined immunodeficient (SCID) mice using techniques previously developed in our laboratory. Growth of xenografts was evaluated by gross examination and histopathologic analysis. Confirmation of the human origin of the tumor outgrowth was obtained using in situ hybridization analysis. By histological evaluation, all of the patients' tumors showed evidence of invasive growth in at least 1 of the mice implanted with portions of each surgical specimen and these tumors remained morphologically similar to the parent tumors for a long period of time. Furthermore, 65% (13/20) of the xenografts grew rapidly enough (i.e., reached a diameter of 1-2 cm within 2-6 months) to allow passage to subsequent SCID mice. Among the passaged xenografts, 3 eventually developed metastases in a distribution pattern similar to that of naturally occurring ovarian cancer and 2 developed ascites without evidence of further metastatic spread. Upon evaluation of sera from tumor-bearing mice, human antibodies presumably derived from immunoglobulin-secreting cells present in the original tumor specimen were identified. In support of this, human B cells and plasma cells could be seen within the tumor xenograft for more than 6 months following implantation. In summary, transplantation of surgical specimens from ovarian cancer patients into SCID mice results in an attractive model for the study of the natural history of ovarian cancer and may also be useful for analysis or new experimental therapeutic approaches for the treatment of this disease.

Complications related to indwelling caval catheters on a gynecologic oncology service.

OBJECTIVE: To assess the rate of complications of indwelling caval catheter (ICC) use on a gynecologic oncology service and to compare complication rates between subcutaneous ports and external catheters. METHODS: A retrospective analysis of 185 patients who underwent 216 ICC placements between April 1, 1987 and April 1, 1997, was performed. Patient and catheter characteristics were analyzed as they related to the rate of pneumothorax, bacteremia, and deep neck and thoracic vein thrombosis (DNVT). RESULTS: A total of 216 ICCs were placed including 152 implanted ports and 64 external catheters. Pneumothorax occurred in 2% of ICC insertions. Bacteremia complicated 16% of ICCs. Multivariate analysis demonstrated that external catheters (P < 0.01) and neutropenia (P < 0.01) were independent risk factors for bacteremia. DNVT complicated 6% of ICCs and was observed significantly (P < 0.02) more frequently among 11 catheters placed in patients with clear cell malignancies of the female reproductive tract. Unplanned catheter removal occurred significantly (P < 0.01) more frequently among patients with external catheters compared to implanted devices. CONCLUSIONS: Implantable ICCs appear to offer a significant advantage compared to external devices with regard to the development of bacteremia and unplanned catheter removal. Though catheter type, neutropenia, and TPN are associated with an increased incidence of bacteremia, multivariate analysis does not include TPN as an independent risk factor for ICC-related bacteremia. A significant increase in the rate of DNVT among a small number of patients with clear cell gynecologic malignancies warrants further study.

Stage I adenocarcinoma of the cervix: does lesion size affect treatment options and prognosis?

A retrospective analysis of 93 patients with International Federation of Gynecology and Obstetrics stage I adenocarcinoma of the cervix was performed to determine the significance of tumor size, patient age, tumor grade, lymph node status, and primary treatment modality as prognostic variables of 5-year survival and 5-year progression-free survival (PFS). Multivariate analysis demonstrated that patient age and tumor grade were significant variables prognostic of survival (p < 0.01 and p = 0.01, respectively). Tumor size was a significant (p < 0.01) prognostic variable of PFS in a multivariate model that included tumor size and patient age. An important advantage in survival and PFS for patients with lesions smaller than 3 cm compared with those patients with lesions 3 cm or more was observed (92% vs. 76% and 89% vs. 67%, respectively). Among surgically treated patients, survival and PFS among patients with lesions smaller than 3 cm were significantly improved compared with patients with tumors 3 cm or more (97% vs. 77% [p = 0.03] and 90% vs. 69% [p = 0.03], respectively). Significant improvement in survival and PFS was observed among patients with lesions smaller than 3 cm who were treated with surgery compared with those who received radiation therapy (97% vs. 77% [p = 0.03] and 90% vs. 77% [p = 0.048], respectively).

The effect of recombinant growth hormone on the strength of ileal anastomoses in a rat model.

OBJECTIVE: In gynecologic surgery, the ileum is the primary site of bowel injury. Recombinant growth hormone (rGH) has been shown to improve the strength of colonic anastomoses in experimental models. The purpose of this study is to evaluate the effect of rGH on small bowel anastomoses, specifically in the ileum. METHODS: Twenty large female rats underwent segmental ileal resections and end-to-end ileoileostomies. The rats were randomized to be treated for 7 postoperative days with either rGH (2.0 mg/kg/day) or placebo starting on the day of surgery. On the seventh postoperative day, a segment of ileum surrounding the anastomosis was resected. The anastomoses were tested for breaking strength on a tensiometer and for tissue concentrations of hydroxyproline. RESULTS: The ileal anastomotic breaking strength in the rGH group was 163.5 +/- 6.0 g (mean +/- standard error). In the placebo group, the breaking strength of ileal anastomoses was 125.0 +/- 3.0 g (P < .001). No significant difference was demonstrated with respect to the hydroxyproline concentration between the rGH group (15.2 +/- 2.0 micrograms/mg) and the placebo group (14.6 +/- 1.0 micrograms/mg). CONCLUSION: In an animal model, a 31% increase in ileal anastomotic breaking strength was induced by rGH administration. With further research this may translate into decreases in the surgical complications that occur in ileal anastomoses. Furthermore, these serve as preliminary data to a study that evaluates the effect of rGH on ileal anastomoses in radiation-injured bowel.

Counseling and peer review are key disciplinary procedures.

The best approach to the problem of an employee with a disciplinary problem is not always termination. When performance slips at this hospital, supervisors work closely with the employee to bring about improvement. The secret to the system is early recognition of problems, followed by intense problem solving.